Heterocyclic compounds useful as inhibitors of tyrosine kinases

ABSTRACT

Disclosed are novel compounds of formula (I):  
                 
 
     wherein Ar 1 , X, Y, P, Q and Het are defined herein, which are useful as inhibitors of certain protein tyrosine kinases and are thus useful for treating diseases resulting from inappropriate cell proliferation, which include autoimmune diseases, chronic inflammatory diseases, allergic diseases, transplant rejection and cancer, as well as conditions resulting from cerebral ischemia, such as stroke. Also disclosed are pharmaceutical compositions comprising these compounds, processes for preparing these compounds and novel intermediate compounds useful in these processes.

[0001] This application claims benefit from U.S. Provisional ApplicationNo. 60/224,724, filed Aug. 11, 2000, which is herein incorporated byreference in its entirety.

FIELD OF THE INVENTION

[0002] This invention relates to substituted compounds of formula (I):

[0003] wherein Ar₁, X, Y, P, Q and Het are defined below, which areuseful as inhibitors of certain protein tyrosine kinases and are thususeful for treating diseases resulting from inappropriate cellproliferation, which include autoimmune diseases, chronic inflammatorydiseases, allergic diseases, transplant rejection and cancer, as well asconditions resulting from cerebral ischemia, such as stroke. Thisinvention also relates to pharmaceutical compositions comprising thesecompounds, methods of using these compounds in the treatment of variousdiseases, processes for preparing these compounds and intermediateuseful in these processes.

BACKGROUND OF THE INVENTION

[0004] Tyrosine kinases play an essential role in the regulation of cellsignaling and cell proliferation by phosphorylating tyrosine residues ofpeptides and proteins. Inappropriate activation of tyrosine kinases isknown to be involved in a variety of disease states, includingimmunologic and oncologic disorders.

[0005] It has been well established that T cells play an important rolein regulating the immune response (F. Powrie and R. L. Coffman, Immunol.Today, 1993, 14, 270). Activation of T cells is often the initiatingevent in many inflammatory and autoimmune diseases. In addition to theirrole in immune surveillance, T cells can become autoreactive byrecognizing self-antigens and thereby cause autoimmune disease such asrheumatoid arthritis and inflammatory bowel disease.

[0006] The T cell receptor (TCR) is the antigen-specific component ofthe T cell and is activated when the receptor is engaged with foreign orself-antigenic peptides. When the TCR is activated a series ofenzyme-mediated signal transduction cascades is initiated which resultsin the production of pro-inflammatory cytokines such as interlukin-2(IL-2). The release of IL-2 is critically important since thislymphokine is required for T-lymphocyte proliferation, differentiation,and effector function. Clinical studies have shown that interferencewith IL-2 activity effectively suppresses immune response in vivo (T. A.Waldmann, Immunol. Today, 1993, 14, 270). Accordingly, agents whichinhibit T-lymphocyte activation and subsequent IL-2 production, or blockthe activity of IL-2 are therapeutically useful for selectivelysuppressing immune response in a patient in need of suchimmunosuppression.

[0007] The eight members of the src family of tyrosine kinases are src,lck, fyn, lyn, hck, fgr, blk and yes (J. B. Bolen, J. S. Brugge, Ann.Rev. Immunol., 1997, 15, 371). These can be divided into 2 groups basedon their pattern of tissue expression. Src, fyn and yes have a broaddistribution while expression of lck, lyn, hck, fgr, and blk is largelylimited to hemopoietic cells. The therapeutic effects of inhibitingkinases of the src family can be ascertained by linking functionaldefects seen in gene disruption studies in mice. Src(-/-) mice hadsevere abnormalities in bone remodeling. Inhibition of src may thereforebe useful in treating osteoporosis. Lck(-/-) mice display a completelack of CD4+ cells are unable to mount antigen-dependent immuneresponses.

[0008] A kinase of particular interest is p56lck, which is onlyexpressed in T-cells. Within the TCR signal transduction cascade thetyrosine kinase p56lck is a required element to initiate the activationresponse from the TCR intracellular domains to other signaling proteins.For example, T cells which lack the p56lck protein are unable to signalthrough the T cell receptor (D. B. Straus and A. Weiss, Cell, 1992, 70,585). Transfection of p56lck back into these cell lines restores TCRresponsiveness. Also, it has been shown in mice that inactivation of thep56lck gene leads to lack of proper thymocyte development (T. J. Molinaet al., Nature, 1992, 357, 161).

[0009] The conclusion drawn from these studies is that p56lck plays acrucial role in T cell maturation and antigen-induced T-cell activation.Therefore, an agent blocking p56lck would effectively block T cellfunction, act as an immunosuppressive agent and have potential utilityin autoimmune diseases, for example rheumatoid arthritis, multiplesclerosis, lupus, transplant rejection and allergic diseases (J. H.Hanke et al., Inflamm. Res., 1995, 44, 357).

[0010] Inhibitors of other members of the src family of non-receptortyrosine kinases are also useful for treating various disease states.Src is present in osteoclasts, and is important in bone remodeling. Forexample, inactivation of p60src diminishes bone resorption byosteoclasts (P. Soriano et al., Cell 1991, 64, 693, B. F. Boyce et al.J. Clin. Invest 1992, 90, 1622), it is therefore possible thatinhibitors of the kinase activity of p60src are useful in the treatmentof osteoporosis, Paget's disease and inflammation of bones and joints.

[0011] Src kinases have been found to be activated in tumors, includingbreast and colon cancers, melanoma and sarcoma. For example, a number ofprimary tumors and tumor cell lines from patients with breast cancer,colon cancer, melanoma and sarcoma have been shown to have elevated srckinase activity, and activating src mutations are seen in some advancedcolon cancers. Inhibitors of src kinase had significantantiproliferative activity against cancer cell lines (M. M. Moasser etal., Cancer Res., 1999, 59, 6145) and inhibited the transformation ofcells to an oncogenic phenotype (R. Karni et al., Oncogene, 1999, 18,4654) suggesting that src kinase inhibitors may be useful anti-canceragents.

[0012] Src inhibitors have also been reported to be effective in ananimal model of cerebral ischemia (R. Paul et al. Nature Medicine 2001,7, 222), suggesting that src kinase inhibitors may thus be useful intreating conditions involving cerebral ischemia. For example, src kinaseinhibitors may be useful in reducing brain damage following stroke.

[0013] In addition, src family kinases participate in signaltransduction in several cell types. For example, fyn, like lck, isinvolved in T-cell activation. Hck and fgr are involved in Fc gammareceptor mediated oxidative burst of neutrophils. Src and lyn arebelieved to be important in Fc epsilon induced degranulation of mastcells, and so may play a role in asthma and other allergic diseases. Thekinase lyn is known to be involved in the cellular response to DNAdamage induced by UV light (T. Hiwasa, FEBS Lett. 1999, 444, 173) orionizing radiation (S. Kumar, J. Biol Chem, 1998, 273, 25654).Inhibitors of lyn kinase may thus be useful as potentiators in radiationtherapy.

[0014] Platelet derived growth factor is a potent mitogen for smoothmuscle cells. Its receptor (PDGFR) is a member of the receptor tyrosinekinase family (L. Claesson-Welsh, J. Biol Chem, 1994, 269, 32023). PDGFis involved in atherosclerosis and restenosis (K. E. Bornfeldt, TrendsCardiovasc. Med., 1996, 6, 143). In addition, receptor tyrosine kinasesincluding PDGFR kinase have been implicated as contributing factors incancer (A. Levitzki and A. Gazit, Science, 1995, 267, 1782) includingovarian (M. B. Dabrow et al., Gynecologic Oncology, 1998, 71, 29) andprostate (S. M. Sintich et al., Endocrinology, 1999, 140, 3411) cancersand glioblastoma (B. J. Silver, BioFactors, 1992 3, 217). Inhibitors ofPDGFR kinase are thus useful in the treatment of fibrotic diseases,restenosis and PDGF-dependent tumors.

[0015] Reports have appeared in the literature of agents that inhibitthe kinase activity of p56lck kinase and thus inhibit T cell activation.These include the natural product lavendustin A, and analogs (M. S.Smyth, J. Med. Chem., 1993, 36, 3010), the natural product damnacanthal(C. R. Faltynek et al., Biochemistry, 1995, 34, 12404), and a 1-methoxyagroclavine isolated from a fungal extract (R. Padmanabha et al.Bioorganic and Med. Chem. Letters, 1998, 8, 569). Other inhibitorsreported include WIN 61651 (J. Enzyme Inhibition, 1995, 9, 111)pyrazolopyrimidines PP1 and PP2 (Hanke et al. J. Biol Chem, 1996, 271,695) and indanone and indandione derivatives (J. L. Bullington et al.,Bioorganic and Med. Chem. Letters, 1998, 8, 2489).

[0016] A. P. Spader et al. (WO 98/54157, 1998) describe quinoline andquinoxaline compounds that inhibit p56lck and PDGFR kinase. Fusedpolycyclic 2-aminopyrimidine derivatives that inhibit p56lck arereported by J. M. Davis et al. (WO 98/28281, 1998). J. Das et al. claima series of benzothiazole amides as inhibitors of lck and other srcfamily kinases (WO 99/24035, 1999). Inhibitors of PDGFR kinase andsrc-family kinases were reviewed by H. D. H. Showalter, A. J. Kraker,Pharmacol. Ther., 1997, 76, 55. Several patents on inhibitors of lck arereviewed in P. M. Traxler, Exp. Opin. Ther. Patents, 1997, 7, 571,and P.M. Traxler, Exp. Opin. Ther. Patents, 1998, 8, 1599.

[0017] EP 322 746 A1 discloses heterocyclic lactam derivatives describedas being useful as cardiotonic agents, antihypertensive agents andvasodilators.

[0018] Examples of tricyclic systems similar to formula (I) above areknown, but not having the 2-amino substituents on the benzimidazolering. See S. W. Schneller et al., J. Med. Chem., 1989, 32, 2247.Examples of tricyclic systems similar to formula (I) with a carbamate atthe 2-position have been reported in S. Kumar et al., Indian J. Chem.1981, 20B, 1068 and S. Agarwal et al., Z. Naturforsch. C, 1993, 48, 829.

[0019] The compounds of the present invention represent a novelstructural class, which is distinct from previously reported tyrosinekinase inhibitors.

BRIEF SUMMARY OF THE INVENTION

[0020] The work cited above supports the principle that inhibition ofthe kinases mentioned above will be beneficial in the treatment ofvarious disease states.

[0021] It is therefore an object of the invention to provide novelcompounds which inhibit PDGFR kinase and the src-family kinasesincluding lck, src, fyn, lyn, hck, fgr, blk and yes.

[0022] It is a further object of the invention to provide methods fortreating diseases and pathological conditions mediated by src-familytyrosine kinases and PDGFR kinase such as autoimmune diseases,transplant rejection, psoriasis, osteoporosis, Paget's disease, cancer,including src-dependent tumors and PDGF-dependent tumors, cerebralischemic conditions, atherosclerosis, restenosis and allergic diseases,using the novel compounds of the invention.

[0023] It is yet a further object of the invention to provide processesof preparation of the above-mentioned novel compounds and pharmaceuticalcompositions comprising the same.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The src-family tyrosine kinases and PDGFR kinase discussed aboveexhibit some homology in their amino acid structure. It is contemplatedthat due to structural differences between individual src-family kinasesand PDGFR kinase, different compounds of the invention may havedifferent inhibitory potencies against individual tyrosine kinases. Thussome of compounds of the invention may also be expected to be mosteffective in treating diseases mediated by tyrosine kinases that theyinhibit most potently. Particular compounds disclosed herein have beenshown to be active inhibitors of p56lck kinase, p60src kinase and PDGFRkinase. See the section entitled “Assessment of Biological Properties”disclosed herein.

[0025] In its broadest generic aspect, the invention provides novelcompounds of the formula (I) below:

[0026] wherein:

[0027] Ar₁ is an aromatic or nonaromatic carbocycle, heteroaryl orheterocycle; wherein said carbocycle, heteroaryl or heterocycle isoptionally substituted by one or more R₁, R₂ and R₃;

[0028] X is NH, N—C₁₋₃alkyl, N-cyclopropyl, S or O;

[0029] Y is NR₁₃;

[0030] R₁ and R₂ are the same or different and are selected from H,halogen, CN, NO₂, C₁₋₁₀ branched or unbranched saturated or unsaturatedalkyl, C₁₋₁₀ branched or unbranched alkoxy, C₁₋₁₀ branched or unbranchedacyl, C₁₋₁₀ branched or unbranched acyloxy, C₁₋₁₀ branched or unbranchedalkylthio, aminosulfonyl, di-(C₁₋₃)alkylaminosulfonyl, NR₈R₉, aryl,aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein theabovementioned R₁ and R₂ are optionally partially or fully halogenatedor optionally substituted with one to three groups independentlyselected from the group consisting of oxo, OH, NR₈R₉, C₁₋₆ branched orunbranched alkyl, C₃₋₇cycloalkyl, phenyl, naphthyl, heteroaryl,aminocarbonyl and mono- or di(C₁₋₃)alkylaminocarbonyl;

[0031] R₃ is selected from the group consisting of H, halogen, OH,(CH₂)_(n)NR₈R₉, (CH₂)_(n)CO₂R₁₀, C₁₋₃alkyl optionally substituted withOH, C₁₋₃ alkoxy optionally halogenated and C₁₋₃ alkylthio;

[0032] Het represents a fused heterocylic ring having a formula A, B orC:

[0033] R₄ is selected from H, C₁₋₆ alkyl branched or unbranched,saturated or unsaturated, and optionally substituted with phenyl, OH orC₁₋₃alkoxy, C₃₋₁₀-cycloalkyl, or C₅₋₈cycloalkenyl; or R₄ is selectedfrom (CH₂)_(m)NR₈R₉, (CH₂)_(m)NR₈COR₁₀, (CH₂)_(n)CO₂R₁₀,(CH₂)_(n)CONR₈R₉, phenyl, heteroaryl or heterocycle, each phenyl ,heteroaryl or heterocycle being optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, (CH₂)_(m)NR₈R₉, OH, SO₃H or halogen;

[0034] R₅ is selected from H, C₁₋₁₀alkyl branched or unbranched,C₃₋₁₀cycloalkyl, C₅₋₇cycloalkenyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆acyl,each being optionally substituted with one or more halogen, OH, oxo, CN,C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₃alkoxy, NR₈R₉, ureido,guanidino, NR₈COR₁₀, SR₁₀, CONR₈R₉, CO₂R₁₀, C₃₋₁₀ cycloalkyl,C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl, aryloxy, arylthio, aryl,heteroaryl or heterocycle; wherein each of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₃ ₁₀cycloalkylidene, C₅₋₇cycloalkenyl,aryloxy, arylthio, aryl, heteroaryl or heterocycle is optionallysubstituted with one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CN, NO₂,amidino, guanidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one ormore of the amino nitrogens in the ureido, amidino or guanidino groupsin this paragraph may be optionally substituted with C₁₋₃alkyl,phenylC₀₋₃alkyl, C₁₋₃alkoxy or CO₂R₁₀;

[0035] or R₅ is selected from CO₂R₁₀, NR₈R₉, CONR₈R₉, aryl, heteroaryl,heterocycle, aryl-CO—, heteroaryl-CO— or heterocycle-CO—, wherein eacharyl, heteroaryl or heterocycle is optionally substituted with one tothree:

[0036] C₁₋₃alkoxy, halogen, NO₂, CN, S(O)_(p)NR₈R₉, C₀₋₃alkylS(O)_(p),NR₈R₉, (CH₂)_(n)CO₂R₁₀, (CH₂)_(n)CONR₈R₉, CO(CH₂)_(n)NR₈R₉,O(CH₂)₂₋₄NR₈R₉, ureido, guanidino, cycloalkyl, aryl, heteroaryl,heterocycle, cycloalkyl-Z-, aryl-Z-, heteroaryl-Z-, heterocycle-Z-, orC₁₋₃alkyl optionally substituted with phenyl or NR₈R₉, wherein Z is abridging group selected from C₁₋₁₀ alkylene branched or unbranched, CO,S(O)_(p), O, S, NH, CONH, NHCO, COO or OOC, and wherein each cycloalkyl,aryl, heteroaryl or heterocycle is optionally substituted with NO₂,C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CO₂R₁₀, (CH₂)_(n)NR₈R₉, O(CH₂)₂₋₄NR₈R₉,ureido or guanidino, wherein one or more of the amino nitrogens in theureido or guanidino groups in this paragraph may be optionallysubstituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy; and whereineach alkyl, alkoxy and phenyl in this paragraph is optionally partiallyor fully halogenated;

[0037] or R₅ is a C₆₋₁₂ bridged- or spiro-bicyclic ring system,optionally having one or two double bonds in the ring system, andwherein up to 3 carbon atoms in the ring system may be replaced byheteroatoms selected from N, O and S; and wherein said ring system maybe optionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CO₂R₁₀,ureido, guanidino, amidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; whereinone or more of the amino nitrogens in the ureido, guanidino or amidinogroups in this paragraph may be optionally substituted with C₁₋₃alkyl,phenylC₀₋₃alkyl or C₁₋₃alkoxy;

[0038] R₆ is selected from H, C₁₋₆alkyl branched or unbranched, C₂₋₆alkenyl branched or unbranched, CO₂R₁₀, C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, aryl, arylC₁₋₃alkyl, heteroaryl and heterocyclyl;wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,aryl, arylC₁₋₃alkyl, heteroaryl or heterocyclyl are optionallysubstituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂,O(CH₂)₂₋₄NR₁₁R₁₂, aryl, heteroaryl or heterocyclyl;

[0039] R₇ is H or C₁₋₆alkyl;

[0040] R₈ and R₉ are the same or different and are each independentlyselected from H, OH, CO₂R₁₀, C₁₋₁₀ acyl branched or unbranched,C₁₋₃alkoxy, C₁₋₆alkyl branched or unbranched,C₃₋₆alkenyl,C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl, heteroaryl orheterocycle; wherein said alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl,heteroaryl or heterocycle are optionally substituted with OH,C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl orheteroaryl;

[0041] or R₈ and R₉ together form a 3-7 member alkylene chain completinga ring about the N atom to which they are attached; wherein saidalkylene chain is optionally interrupted by O, S(O)_(p), NCOR₁₀,NCO₂R₁₀, NR₁₁ or NC(═NR₁₁)NR₁₁R₁₂; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₁R₁₂;

[0042] R₁₀ is selected from H, C₁₋₆alkyl, C₃₋₈cycloalkyl, wherein eachalkyl or cycloalkyl is optionally substituted with phenyl, OH,C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂, or R₁₀ is phenyl optionallysubstituted with one to three C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(m)NR₈R₉, (CH₂)_(n)CONR₈R₉ or O(CH₂)₂₋₄NR₈R₉;

[0043] R₁₁ and R₁₂ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0044] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂;

[0045] R₁₃ is H or C₁₋₃alkyl;

[0046] P and Q are each independently CH or N;

[0047] m is 1-4;

[0048] n is 0-3;

[0049] and p is 0-2;

[0050] wherein one or more of the primary amine or secondary aminenitrogen atoms in any of the R₄, R₅, R₆ and R₇ substituent groups mayoptionally be protected by a protecting group;

[0051] and the pharmaceutically acceptable derivatives thereof.

[0052] In one embodiment of the invention, there are provided compoundsof the formula (I) as described above, and wherein:

[0053] Ar₁ is

[0054] a) a cycloalkyl group selected from cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl and cycloheptanyl;

[0055] b) a cycloalkenyl group selected from cyclopentenyl,cyclohexenyl, and cycloheptenyl;

[0056] c) an aromatic carbocycle selected from phenyl, naphthyl,indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl,

[0057] d) a heteroaryl selected from pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl,or a fusedheteroaryl selected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine,cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine,cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline,cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole,cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or

[0058] e) a heterocycle selected from: pyrrolinyl, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,pyranyl, thiopyranyl, piperazinyl and indolinyl;

[0059] wherein each of the above Ar₁ are optionally substituted by oneor more R₁, R₂ and R₃;

[0060] R₁ and R₂ are as defined in claim 1, and R₃ is hydrogen, halogen,methyl, methoxy, hydroxymethyl or OH;

[0061] wherein each of the above Ar₁ are optionally substituted by oneor more R₁, R₂ and R₃;

[0062] R₁ and R₂ are as defined in claim 1, and R₃ is H, halogen,methyl, methoxy, hydroxymethyl or OH;

[0063] R₄ is H, C₁₋₃alkyl branched or unbranched, saturated orunsaturated, and optionally substituted with OH; or R₄ is (CH₂)₂₋₃NR₈R₉,(CH₂)_(n)CO₂R₁₀ or (CH₂)_(n)CONR₈R₉;

[0064] R₅ is selected from H, C₁₋₁₀alkyl branched or unbranched, C₃₋₁₀cycloalkyl, C₅₋₇cycloalkenyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆acyl, eachbeing optionally substituted with one or more halogen, OH, oxo, CN,C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₃alkoxy, NR₈R₉, ureido,guanidino, NR₈COR₁₀, SR₁₀, CONR₈R₉, CO₂R₁₀, C₃₋₁₀cycloalkyl,C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl, aryloxy, arylthio, aryl,heteroaryl or heterocycle; wherein each of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl,aryloxy, arylthio, aryl, heteroaryl or heterocycle is optionallysubstituted with one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CN, NO₂,amidino, guanidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one ormore of the amino nitrogens in the ureido, amidino or guanidino groupsin this paragraph may be optionally substituted with C₁₋₃alkyl,phenylC₀₋₃alkyl, C₁₋₃alkoxy or CO₂R₁₀;

[0065] or R₅ is selected from CO₂R₁₀, NR₈R₉, CONR₈R₉, aryl, heteroaryl,heterocycle, aryl-CO—, heteroaryl-CO— or heterocycle-CO—, wherein eacharyl, heteroaryl or heterocycle is optionally substituted with one tothree:

[0066] C₁₋₃alkoxy, halogen, NO₂, CN, S(O)_(p)NR₈R₉, CO₀₋₃alkylS(O)_(p),NR₈R₉, (CH₂)_(n)CO₂R₁₀,(CH₂)_(n)CONR₈R₉,CO(CH₂)_(n)NR₈R₉,O(CH₂)₂₋₄NR₈R₉, ureido, guanidino,cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkyl-Z-, aryl-Z-,heteroaryl-Z-, heterocycle-Z-, or C₁₋₃alkyl optionally substituted withphenyl or NR₈R₉, wherein Z is a bridging group selected from C₁₋₁₀alkylene branched or unbranched, CO, S(O)_(p), O, S, NH, CONH, NHCO, COOor OOC, and wherein each cycloalkyl, aryl, heteroaryl or heterocycle isoptionally substituted with NO₂, C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CO₂R₁₀,(CH₂)_(n)NR₈R₉, O(CH₂)₂₋₄NR₈R₉, ureido or guanidino, wherein one or moreof the amino nitrogens in the ureido or guanidino groups in thisparagraph may be optionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkylor C₁₋₃alkoxy; and wherein each alkyl, alkoxy and phenyl in thisparagraph is optionally partially or fully halogenated;

[0067] or R₅ is a C₆₋₁₂ bridged- or spiro-bicyclic ring system,optionally having one or two double bonds in the ring system, andwherein up to 3 carbon atoms in the ring system may be replaced byheteroatoms selected from N, O and S; and wherein said ring system maybe optionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CO₂R₁₀,ureido, guanidino, amidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; whereinone or more of the amino nitrogens in the ureido, guanidino or amidinogroups in this paragraph may be optionally substituted with C₁₋₃alkyl,phenylC₀₋₃alkyl or C₁₋₃alkoxy;

[0068] R₆ is selected from H, C₁₋₆alkyl branched or unbranched, C₂₋₆alkenyl branched or unbranched, or CO₂R₁₀; wherein said C₁₋₆alkyl orC₁₋₆ alkenyl are optionally substituted with OH, C₁₋₃alkoxy,C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl, heteroaryl orheterocyclyl;

[0069] R₇ is H or C₁₋₆alkyl;

[0070] R₈ and R₉ are the same or different and are each independentlyselected from H, OH, C₁₋₃alkyl branched or unbranched, CO₂R₁₀,C₃₋₈cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl or heterocycle;wherein said alkyl, cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl orheterocycle are optionally substituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy,CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl or heteroaryl;

[0071] or R₈ and R₉ together form a 3-7 member alkylene chain completinga ring about the N atom to which they are attached; wherein saidalkylene chain is optionally interrupted by O, S(O)_(p), NCOR₁₀,NCO₂R₁₀, NR₁₁ or NC(═NR₁₁)NR₁₁R₁₂; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₁R₁₂;

[0072] R₁₀ is H or C₁₋₆alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂;

[0073] R₁₁ and R₁₂ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0074] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂;

[0075] R₁₃ is H; and

[0076] P and Q are each CH.

[0077] In another embodiment of the invention, there are providedcompounds of the formula (I) as described immediately above, andwherein:

[0078] Ar₁ is phenyl or pyridyl, each optionally subsituted by one ormore R₁, R₂ and R₃;

[0079] X is NH or N—C₁₋₃alkyl;

[0080] Y is NH;

[0081] R₁ and R₂ are the same or different and selected from: halogen,C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally partially or fullyhalogenated, NO₂ or NR₈R₉;

[0082] R₃ is H, halogen, methyl or methoxy;

[0083] R₄ is H, C₁₋₃alkyl branched or unbranched, saturated orunsaturated, and optionally substituted with OH; or R₄ is (CH₂)₂₋₃NR₈R₉or CO₂R₁₀;

[0084] R₅ is selected from H, C₁₋₃alkyl branched or unbranched, C₃₋₈cycloalkyl, C₅₋₇cycloalkenyl or C₂₋₄ alkenyl, each being optionallysubstituted with one or more OH, CN, NR₈R₉, CONR₈R₉, C₃₋₈ cycloalkyl,C₅₋₇cycloalkenyl, phenyl, heteroaryl or heterocycle; wherein eachphenyl, heteroaryl or heterocycle is optionally substituted with one ormore C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CN, NO₂, amidino, guanidino,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one or more of the aminonitrogens in the amidino or guanidino groups in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl, C₁₋₃alkoxy orCO₂R₁₀;

[0085] or R₅ is selected from CO₂R₁₀, NR₈R₉, CONR₈R₉, phenyl, furyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl,benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl, or indolyl-CO-,wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, benzofuranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl,pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl orindolyl-CO— is optionally substituted with one to three:

[0086] halogen, NO₂, S(O)_(p)NR₈R₉, C₀₋₃alkylS(O)_(p), NR₈R₉,(CH₂)_(n)CO₂R₁₀, ureido, guanidino, cycloalkyl, phenyl, heteroaryl,heterocycle, cycloalkyl-Z-, phenyl-Z-, heteroaryl-Z-, heterocycle-Z-, orC₁₋₃alkyl optionally substituted with phenyl or NR₈R₉, wherein Z is abridging group selected from C₁₋₃ alkylene branched or unbranched, O,S(O)_(p) or NH, and wherein each cycloalkyl, phenyl, heteroaryl orheterocycle is optionally substituted with NO₂, C₁₋₃alkyl, C₁₋₃alkoxy,CO₂R₁₀, (CH₂)_(n)NR₈R₉, O(CH₂)₂₋₄NR₈R₉ or guanidino, wherein one or moreof the amino nitrogens in the guanidino group in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy;and wherein each alkyl, alkoxy and phenyl in this paragraph isoptionally partially or fully halogenated;

[0087] or R₅ is a C₆₋₇ bridged-bicyclic ring system, optionally havingone or two double bonds in the ring system, and wherein up to 1 carbonatom in the ring system may be replaced by a nitrogen atom; and whereinsaid ring system may be optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, halogen, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉;

[0088] R₆ is selected from H, C₁₋₆alkyl branched or unbranched orCO₂R₁₀;

[0089] R₇ is H or C₁₋₆alkyl;

[0090] R₈ and R₉ are the same or different and are each independentlyselected from H, C₁₋₃alkyl branched or unbranched, CO₂R₁₀, phenyl, orbenzoyl; wherein said alkyl, phenyl or benzoyl are optionallysubstituted with OH or C₁₋₃alkoxy;

[0091] or R₈ and R₉ together form a —(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂— group, a—(CH₂)₂—N(COR₁₀)—(CH₂)₂— group, a —(CH₂)₂—N(R₁₁)—(CH₂)₂— group or a—(CH₂)₂—N(C(═NR₁₁)NR₁₁R₁₂)—(CH₂)₂— group; and wherein said ring isoptionally substituted by C₁₋₃ alkyl, C₁₋₃alkoxy, or OH;

[0092] R₁₀ is H or C₁₋₆alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂;

[0093] R₁₁ and R₁₂ are each independently selected from H and C₁₋₃ alkyloptionally substituted with C₁₋₃alkoxy or OH;

[0094] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂.

[0095] In yet another embodiment of the invention there are providedcompounds of the formula (I) as described immediately above, andwherein:

[0096] Ar₁ is phenyl;

[0097] R₁ and R₂ are the same or different and selected from: halogen,methyl optionally partially or fully halogenated, NO₂ and NH₂;

[0098] R₃ is H, chloro, fluoro, bromo or methoxy;

[0099] R₅ is selected from C₂₋₄ alkenyl, C₃₋₈ cycloalkyl orC₅₋₇cycloalkenyl, each being optionally substituted with one or more OH,CN, NR₈R₉, CONR₈R₉ or phenyl; wherein phenyl is optionally substitutedwith one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen, amidino, guanidino,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one or more of the aminonitrogens in the amidino or guanidino groups in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy;

[0100] or R₅ is selected from phenyl, furyl, thienyl, oxazolyl,thiazolyl , pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl,pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl orindolyl-CO—, wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl,pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, or indolyl-CO— isoptionally substituted with one to two:

[0101] halogen, NO₂, SO₂NR₈R₉, NR₈R₉, (CH₂)_(n)CO₂R₁₀, ureido,cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Z-,heteroaryl-Z- or heterocycle-Z-, or C₁₋₃alkyl optionally substitutedwith NR₈R₉, wherein Z is a bridging group selected from C₁₋₃ alkylenebranched or unbranched, wherein each cycloalkyl, phenyl, heteroaryl orheterocycle is optionally substituted with NO₂, C₁₋₃alkyl, CO₂R₁₀, NR₈R₉or guanidino, wherein one or more of the amino nitrogens in theguanidino group in this paragraph may be optionally substituted withC₁₋₃alkyl; and wherein each alkyl and phenyl in this paragraph isoptionally partially or fully halogenated;

[0102] or R₅ is a 7-azabicyclo[2.2.1]heptane ring system, optionallyhaving one or two double bonds in the ring system, wherein said ringsystem may be optionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy,halogen, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉;

[0103] R₆ is selected from H or C₁₋₃alkyl branched or unbranched;

[0104] R₇ is H or C₁₋₃alkyl;

[0105] R₈ and R₉ are the same or different and are each independentlyselected from H or C₁₋₃alkyl branched or unbranched; wherein said alkylis optionally substituted with OH or C₁₋₃alkoxy;

[0106] or R₈ and R₉ together form a —(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂—, a—(CH₂)₂—N(COR₁₀)—(CH₂)₂— group, a —(CH₂)₂—N(R₁₁)—(CH₂)₂— group or a—(CH₂)₂—N(C(═NR₁₁)NR₁₁R₁₂)—(CH₂)₂— group; and wherein said ring isoptionally substituted by C₁₋₃ alkyl, C₁₋₃alkoxy, or OH;

[0107] R₁₀ is H or C₁₋₃alkyl optionally substituted with phenyl, OH orC₁₋₃alkanoyloxy; and

[0108] R₁₁ is selected from H and C₁₋₃alkyl.

[0109] In yet another embodiment of the invention, there are providedany of the compounds of formula (I) described above wherein Hetrepresents a fused ring having formula B:

[0110] In still another embodiment of the invention, there are providedcompounds of the formula (I′) below:

[0111] wherein:

[0112] X is NH, N—C₁₋₃alkyl, N-cyclopropyl, S or O;

[0113] R₁ and R₂ are the same or different and are selected from H,halogen, CN, NO₂, C₁₋₁₀ branched or unibranched saturated or unsaturatedalkyl, C₁₋₁₀ branched or unbranched alkoxy, C₁₋₁₀ branched or unbranchedacyl, C₁₋₁₀ branched or unbranched acyloxy, C₁₋₁₀ branched or unbranchedalkylthio, aminosulfonyl, di-(C₁₋₃)alkylaminosulfonyl, NR₈R₉, aryl,aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein theabovementioned R₁ and R₂ are optionally partially or fully halogenatedor optionally substituted with one to three groups independentlyselected from the group consisting of oxo, OH, NR₈R₉, C₁₋₆ branched orunbranched alkyl, C₃₋₇cycloalkyl, phenyl, naphthyl, heteroaryl,aminocarbonyl and mono- or di(C₁₋₃)alkylaminocarbonyl;

[0114] R₃ is selected from the group consisting of H, halogen, OH,(CH₂)_(n)NR₈R₉, (CH₂)_(n)CO₂R₁₀, C₁₋₃alkyl optionally substituted withOH, C₁₋₃ alkoxy optionally halogenated and C₁₋₃ alkylthio;

[0115] Het represents a fused heterocyclic ring having a formula A, B orC:

[0116] R₄ is selected from H, C₁₋₆ alkyl branched or unbranched,saturated or unsaturated, and optionally substituted with phenyl, OH orC₁₋₃alkoxy, C₃₋₁₀-cycloalkyl, or C₅₋₈cycloalkenyl; or R₄ is selectedfrom (CH₂)_(m)NR₈R₉, (CH₂)_(m)NR₈COR₁₀, (CH₂)_(n)CO₂R₁₀,(CH₂)_(n)CONR₈R₉, phenyl, heteroaryl or heterocycle, each phenyl ,heteroaryl or heterocycle being optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, (CH₂)_(m)NR₈R₉, OH, SO₃H or halogen;

[0117] R₅ is selected from H, C₁₋₁₀alkyl branched or unbranched, C₃₋₁₀cycloalkyl, C₅₋₇cycloalkenyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆acyl, eachbeing optionally substituted with one or more halogen, OH, oxo, CN,C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₃alkoxy, NR₈R₉, ureido,guanidino, NR₈COR₁₀, SR₁₀, CONR₈R₉, CO₂R₁₀, C₃₋₁₀ cycloalkyl,C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl, aryloxy, arylthio, aryl,heteroaryl or heterocycle; wherein each of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl,aryloxy, arylthio, aryl, heteroaryl or heterocycle is optionallysubstituted with one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CN, NO₂,amidino, guanidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one ormore of the amino nitrogens in the ureido, amidino or guanidino groupsin this paragraph may be optionally substituted with C₁₋₃alkyl,phenylC₀₋₃alkyl, C₁₋₃alkoxy or CO₂R₁₀;

[0118] or R₅ is selected from CO₂R₁₀, NR₈R₉, CONR₈R₉, aryl, heteroaryl,heterocycle, aryl-CO—, heteroaryl-CO— or heterocycle-CO—, wherein eacharyl, heteroaryl or heterocycle is optionally substituted with one tothree:

[0119] C₁₋₃alkoxy, halogen, NO₂, CN, S(O)_(p)NR₈R₉, C₀₋₃alkylS(O)_(p),NR₈R₉, (CH₂)_(n)CO₂R₁₀, (CH₂)_(n)CONR₈R₉, CO(CH₂)_(n)NR₈R₉,O(CH₂)₂₋₄NR₈R₉, ureido, guanidino, cycloalkyl, aryl, heteroaryl,heterocycle, cycloalkyl-Z-, aryl-Z-, heteroaryl-Z-, heterocycle-Z-, orC₁₋₃alkyl optionally substituted with phenyl or NR₈R₉, wherein Z is abridging group selected from C₁₋₁₀ alkylene branched or unbranched, CO,S(O)_(p), O, S, NH, CONH, NHCO, COO or OOC, and wherein each cycloalkyl,aryl, heteroaryl or heterocycle is optionally substituted with NO₂,C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CO₂R₁₀, (CH₂)_(n)NR₈R₉, O(CH₂)₂₋₄NR₈R₉,ureido or guanidino, wherein one or more of the amino nitrogens in theureido or guanidino groups in this paragraph may be optionallysubstituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy; and whereineach alkyl, alkoxy and phenyl in this paragraph is optionally partiallyor fully halogenated;

[0120] or R₅ is a C₆₋₁₂ bridged- or spiro-bicyclic ring system,optionally having one or two double bonds in the ring system, andwherein up to 3 carbon atoms in the ring system may be replaced byheteroatoms selected from N, O and S; and wherein said ring system maybe optionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CO₂R₁₀,ureido, guanidino, amidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; whereinone or more of the amino nitrogens in the ureido, guanidino or amidinogroups in this paragraph may be optionally substituted with C₁₋₃alkyl,phenylC₀₋₃alkyl or C₁₋₃alkoxy;

[0121] R₆ is selected from H, C₁₋₆alkyl branched or unbranched, C₂₋₆alkenyl branched or unbranched, CO₂R₁₀, C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, aryl, arylC₁₋₃alkyl, heteroaryl and heterocyclyl;wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,aryl, arylC₁₋₃alkyl, heteroaryl or heterocyclyl are optionallysubstituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂,O(CH₂)₂₋₄NR₁₁R₁₂, aryl, heteroaryl or heterocyclyl;

[0122] R₇ is H or C₁₋₆alkyl;

[0123] R₈ and R₉ are the same or different and are each independentlyselected from H, OH, CO₂R₁₀, C₁₋₁₀ acyl branched or unbranched,C₁₋₃alkoxy, C₁₋₆alkyl branched or unbranched,C₃₋₆alkenyl,C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl, heteroaryl orheterocycle; wherein said alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl,heteroaryl or heterocycle are optionally substituted with OH,C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl orheteroaryl;

[0124] or R₈ and R₉ together form a 3-7 member alkylene chain completinga ring about the N atom to which they are attached; wherein saidalkylene chain is optionally interrupted by O, S(O)_(p), NCOR₁₀,NCO₂R₁₀, NR₁₁ or NC(═NR₁₁)NR₁₁R₁₂; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₁R₁₂;

[0125] R₁₀ is selected from H, C₁₋₆alkyl, C₃₋₈cycloalkyl, wherein eachalkyl or cycloalkyl is optionally substituted with phenyl, OH,C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂, or R₁₀ is phenyl optionallysubstituted with one to three C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(m)NR₈R₉, (CH₂)_(n)CONR₈R₉ or O(CH₂)₂₋₄NR₈R₉;

[0126] R₁₁ and R₁₂ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0127] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂;

[0128] R₁₃ is H or C₁₋₃alkyl;

[0129] P and Q are each independently CH or N;

[0130] m is 1-4;

[0131] n is 0-3;

[0132] and p is 0-2;

[0133] wherein one or more of the primary amine or secondary aminenitrogen atoms in any of the R₄, R₅, R₆ and R₇ substituent groups mayoptionally be protected by a protecting group;

[0134] and the pharmaceutically acceptable derivatives thereof.

[0135] In another embodiment of the invention there are providedcompounds of the formula(I′) as described above, and wherein:

[0136] X is NH or N—C₁₋₃alkyl;

[0137] R₁ and R₂ are the same or different and selected from: halogen,C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally partially or fullyhalogenated, NO₂ or NR₈R₉;

[0138] R₃ is H, halogen, methyl or methoxy;

[0139] R₄ is H, C₁₋₃alkyl branched or unbranched, saturated orunsaturated, and optionally substituted with OH; or R₄ is (CH₂)₂₋₃NR₈R₉or CO₂R₁₀;

[0140] R₅ is selected from H, C₁₋₃alkyl branched or unbranched, C₃₋₈cycloalkyl, C₅₋₇cycloalkenyl or C₂₋₄ alkenyl, each being optionallysubstituted with one or more OH, CN, NR₈R₉, CONR₈R₉, C₃₋₈ cycloalkyl,C₅₋₇cycloalkenyl, phenyl, heteroaryl or heterocycle; wherein eachphenyl, heteroaryl or heterocycle is optionally substituted with one ormore C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CN, NO₂, amidino, guanidino,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one or more of the aminonitrogens in the amidino or guanidino groups in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl, C₁₋₃alkoxy orCO₂R₁₀;

[0141] or R₅ is selected from CO₂R₁₀, NR₈R₉, CONR₈R₉, phenyl, furyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl,benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl, or indolyl-CO—,wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, benzofaranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl,pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl orindolyl-CO— is optionally substituted with one to three:

[0142] halogen, NO₂, S(O)_(p)NR₈R₉, C₀₋₃alkylS(O)_(p), NR₈R₉,(CH₂)_(n)CO₂R₁₀, ureido, guanidino, cycloalkyl, phenyl, heteroaryl,heterocycle, cycloalkyl-Z-, phenyl-Z-, heteroaryl-Z-, heterocycle-Z-, orC₁₋₃alkyl optionally substituted with phenyl or NR₈R₉, wherein Z is abridging group selected from C₁₋₃ alkylene branched or unbranched, O,S(O)_(p) or NH, and wherein each cycloalkyl, phenyl, heteroaryl orheterocycle is optionally substituted with NO₂, C₁₋₃alkyl, C₁₋₃alkoxy,CO₂R₁₀, (CH₂)_(n)NR₈R₉, O(CH₂)₂₋₄NR₈R₉ or guanidino, wherein one or moreof the amino nitrogens in the guanidino group in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy;and wherein each alkyl, alkoxy and phenyl in this paragraph isoptionally partially or fully halogenated;

[0143] or R₅ is a C₆₋₇ bridged-bicyclic ring system, optionally havingone or two double bonds in the ring system, and wherein up to 1 carbonatom in the ring system may be replaced by a nitrogen atom; and whereinsaid ring system may be optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, halogen, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉;

[0144] R₆ is selected from H, C₁₋₆alkyl branched or unbranched orCO₂R₁₀;

[0145] R₇ is H or C₁₋₆alkyl;

[0146] R₈ and R₉ are the same or different and are each independentlyselected from H, C₁₋₃alkyl branched or unbranched, CO₂R₁₀, phenyl, orbenzoyl; wherein said alkyl, phenyl or benzoyl are optionallysubstituted with OH or C₁₋₃alkoxy;

[0147] or R₈ and R₉ together form a —(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂— group, a—(CH₂)₂—N(COR₁₀)—(CH₂)₂— group, a —(CH₂)₂—N(R₁₁)—(CH₂)₂— group or a—(CH₂)₂—N(C(═NR₁₁)NR₁₁R₁₂)—(CH₂)₂— group; and wherein said ring isoptionally substituted by C₁₋₃ alkyl, C₁₋₃alkoxy, or OH;

[0148] R₁₀ is H or C₁₋₆alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂;

[0149] R₁₁ and R₁₂ are each independently selected from H and C₁₋₃ alkyloptionally substituted with C₁₋₃alkoxy or OH;

[0150] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂; and

[0151] P and Q are each CH.

[0152] In still a further embodiment of the invention there are providedcompounds of the formula (I′) as described immediately above, andwherein:

[0153] R₁ and R₂ are the same or different and selected from: halogen,methyl optionally partially or fully halogenated, NO₂ and NH₂;

[0154] R₃ is H, chloro, fluoro, bromo or methoxy;

[0155] R₅ is selected from C₂₋₄ alkenyl, C₃₋₈ cycloalkyl orC₅₋₇cycloalkenyl, each being optionally substituted with one or more OH,CN, NR₈R₉, CONR₈R₉ or phenyl; wherein phenyl is optionally substitutedwith one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen, amidino, guanidino,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one or more of the aminonitrogens in the amidino or guanidino groups in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy;

[0156] or R₅ is selected from phenyl, furyl, thienyl, oxazolyl,thiazolyl , pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl,pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl orindolyl-CO—, wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl,pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-CO— isoptionally substituted with one to two:

[0157] halogen, NO₂, SO₂NR₈R₉, NR₈R₉, (CH₂)_(n)CO₂R₁₀, ureido,cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Z-,heteroaryl-Z- or heterocycle-Z-, or C₁₋₃alkyl optionally substitutedwith NR₈R₉, wherein Z is a bridging group selected from C₁₋₃ alkylenebranched or unbranched or S(O)_(p), wherein each cycloalkyl, phenyl,heteroaryl or heterocycle is optionally substituted with NO₂, C₁₋₃alkyl,CO₂R₁₀, NR₈R₉ or guanidino, wherein one or more of the amino nitrogensin the guanidino group in this paragraph may be optionally substitutedwith C₁₋₃alkyl; and wherein each alkyl and phenyl in this paragraph isoptionally partially or fully halogenated;

[0158] or R₅ is a 7-azabicyclo[2.2.1]heptane ring system, optionallyhaving one or two double bonds in the ring system, wherein said ringsystem may be optionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy,halogen, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉;

[0159] R₆ is selected from H or C₁₋₃alkyl branched or unbranched;

[0160] R₇ is H or C₁₋₃alkyl;

[0161] R₈ and R₉ are the same or different and are each independentlyselected from H or C₁₋₃alkyl branched or unbranched; wherein said alkylis optionally substituted with OH or C₁₋₃alkoxy;

[0162] or R₈ and R₉ together form a —(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂—, a—(CH₂)₂—N(COR₁₀)—(CH₂)₂— group, a —(CH₂)₂—N(R₁₁)—(CH₂)₂— group or a—(CH₂)₂—N(C(═NR₁₁)NR₁₁R₁₂)—(CH₂)₂— group; and wherein said ring isoptionally substituted by C₁₋₃ alkyl, C₁₋₃alkoxy, or OH;

[0163] R₁₀ is H or C₁₋₃alkyl optionally substituted with phenyl, OH orC₁₋₃alkanoyloxy; and

[0164] R₁₁ is selected from H and C₁₋₃ alkyl.

[0165] In yet another embodiment of the invention, there are providedany of the compounds of formula (I′) described above wherein Hetrepresents a fused ring having formula B:

[0166] In yet another aspect of the invention, there are providedcompounds of the following formula Ib:

[0167] wherein R is H, C₁₋₃alkyl or cyclopropyl, and Ar₁ and R₅ are asdefined in formula (I) above.

[0168] The present invention is also directed to the intermediatecompounds of the following formulae (VI), (XII), (XVIII) and (XIX)useful in the synthetic schemes and examples set forth below.

Formula (VI)

[0169] In their broadest generic aspect, intermediate compounds of theformula (VI) are represented by the following formula:

[0170] wherein:

[0171] R is H, C₁₋₃alkyl or cyclopropyl;

[0172] R₄ is selected from H, C₁₋₆ alkyl branched or unbranched,saturated or unsaturated, and optionally substituted with phenyl, OH orC₁₋₃alkoxy; or R₄ is selected from (CH₂)_(m)NR₈R₉, (CH₂)_(m)NR₈COR₁₀,(CH₂)_(n)CO₂R₁₀ or (CH₂)_(n)CONR₈R₉;

[0173] R₈ and R₉ are the same or different and are each independentlyselected from H, OH, CO₂R₁₀, C₁₋₁₀ acyl branched or unbranched,C₁₋₃alkoxy, C₁₋₆alkyl branched or unbranched,C₃₋₆alkenyl,C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl, heteroaryl orheterocycle; wherein said alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl,heteroaryl or heterocycle are optionally substituted with OH,C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl orheteroaryl;

[0174] or R₈ and R₉ together form a 3-7 member alkylene chain completinga ring about the N atom to which they are attached; wherein saidalkylene chain is optionally interrupted by O, S(O)_(p), NCOR₁₀,NCO₂R₁₀, NR₁₁ or NC(═NR₁₁)NR₁₁R₁₂; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₁R₁₂;

[0175] R₁₀ is selected from H, C₁₋₆alkyl, C₃₋₈cycloalkyl, wherein eachalkyl or cycloalkyl is optionally substituted with phenyl, OH,C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂, or R₁₀ is phenyl optionallysubstituted with one to three C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(m)NR₈R₉, (CH₂)_(n)CONR₈R₉ or O(CH₂)₂₋₄NR₈R₉;

[0176] R₁₁ and R₁₂ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0177] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂;

[0178] m is 1-4;

[0179] n is 1-3;

[0180] and p is 0-2;

[0181] wherein one or more of the primary amine or secondary aminenitrogen atoms in the R₄ substituent group may optionally be protectedby a protecting group.

[0182] One embodiment of the compounds of formula(VI) are those wherein:

[0183] R is H or C₁₋₃alkyl; and

[0184] P₄ is H, C₁₋₃alkyl branched or unbranched, saturated orunsaturated, and optionally substituted with OH; or R₄ is (CH₂)₂₋₃NR₈R₉,(CH₂)_(n)CO₂R₁₀ or (CH₂)_(n)CONR₈R₉.

Formula (XII)

[0185] In their broadest generic aspect, intermediate compounds offormula (XII) are represented by the following formula:

[0186] wherein:

[0187] R is H, C₁₋₃alkyl or cyclopropyl; and

[0188] R₅ is selected from H, C₁₋₁₀alkyl branched or unbranched,C₃₋₁₀cycloalkyl, C₅₋₇cycloalkenyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆acyl,each being optionally substituted with one or more halogen, OH, oxo, CN,C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₃alkoxy, NR₈R₉, ureido,guanidino, NR₈COR₁₀, SR₁₀, CONR₈R₉, CO₂R₁₀, C₃₋₁₀ cycloalkyl,C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl, aryloxy, arylthio, aryl,heteroaryl or heterocycle; wherein each of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl,aryloxy, arylthio, aryl, heteroaryl or heterocycle is optionallysubstituted with one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CN, NO₂,amidino, guanidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one ormore of the amino nitrogens in the ureido, amidino or guanidino groupsin this paragraph may be optionally substituted with C₁₋₃alkyl,phenylC₀₋₃alkyl, C₁₋₃alkoxy or CO₂R₁₀;

[0189] or R₅ is selected from CO₂R₁₀, NR₈R₉, CONR₈R₉, aryl, heteroaryl,heterocycle, aryl-CO—, heteroaryl-CO— or heterocycle-CO—, wherein eacharyl, heteroaryl or heterocycle is optionally substituted with one tothree:

[0190] C₁₋₃alkoxy, halogen, NO₂, CN, S(O)_(p)NR₈R₉, C₀₋₃alkylS(O)_(p),NR₈R₉, (CH₂)_(n)CO₂R₁₀, (CH₂)_(n)CONR₈R₉, CO(CH₂)_(n)NR₈R₉,O(CH₂)₂₋₄NR₈R₉, ureido, guanidino, cycloalkyl, aryl, heteroaryl,heterocycle, cycloalkyl-Z-, aryl-Z-, heteroaryl-Z-, heterocycle-Z-, orC₁₋₃alkyl optionally substituted with phenyl or NR₈R₉, wherein Z is abridging group selected from C₁₋₁₀ alkylene branched or unbranched, CO,S(O)_(p), O, S, NH, CONH, NHCO, COO or OOC, and wherein each cycloalkyl,aryl, heteroaryl or heterocycle is optionally substituted with NO₂,C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CO₂R₁₀, (CH₂)_(n)NR₈R₉, O(CH₂)₂₋₄NR₈R₉,ureido or guanidino, wherein one or more of the amino nitrogens in theureido or guanidino groups in this paragraph may be optionallysubstituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy; and whereineach alkyl, alkoxy and phenyl in this paragraph is optionally partiallyor fully halogenated;

[0191] or R₅ is a C₆₋₁₂ bridged- or spiro-bicyclic ring system,optionally having one or two double bonds in the ring system, andwherein up to 3 carbon atoms in the ring system may be replaced byheteroatoms selected from N, O and S; and wherein said ring system maybe optionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CO₂R₁₀,ureido, guanidino, amidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; whereinone or more of the amino nitrogens in the ureido, guanidino or amidinogroups in this paragraph may be optionally substituted with C₁₋₃alkyl,phenylC₀₋₃alkyl or C₁₋₃alkoxy;

[0192] R₆ is selected from H, C₁₋₆alkyl branched or unbranched, C₂₋₆alkenyl branched or unbranched, CO₂R₁₀, C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, aryl, arylC-₁₋₃alkyl, heteroaryl and heterocyclyl;wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,aryl, arylC₁₋₃alkyl, heteroaryl or heterocyclyl are optionallysubstituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂,O(CH₂)₂₋₄NR₁₁R₁₂, aryl, heteroaryl or heterocyclyl;

[0193] R₇ is H or C₁₋₆alkyl;

[0194] R₈ and R₉ are the same or different and are each independentlyselected from H, OH, CO₂R₁₀, C₁₋₁₀ acyl branched or unbranched,C₁₋₃alkoxy, C₁₋₆alkyl branched or unbranched,C₃₋₆alkenyl,C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl, heteroaryl orheterocycle; wherein said alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl,heteroaryl or heterocycle are optionally substituted with OH,C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl orheteroaryl;

[0195] or R₈ and R₉ together form a 3-7 member alkylene chain completinga ring about the N atom to which they are attached; wherein saidalkylene chain is optionally interrupted by O, S(O)_(p), NCOR₁₀,NCO₂R₁₀, NR₁₁ or NC(═NR₁₁)NR₁₁R₁₂; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₁R₁₂;

[0196] R₁₀ is selected from H, C₁₋₆alkyl, C₃₋₈cycloalkyl, wherein eachalkyl or cycloalkyl is optionally substituted with phenyl, OH,C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂, or R₁₀ is phenyl optionallysubstituted with one to three C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(m)NR₈R₉, (CH₂)_(n)CONR₈R₉ or O(CH₂)₂₋₄NR₈R₉;

[0197] R₁₁ and R₁₂ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0198] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂;

[0199] m is 1-4;

[0200] n is 0-3;

[0201] and p is 0-2;

[0202] wherein one or more of the primary amine or secondary aminenitrogen atoms in any of the R₄, R₅, R₆ and R₇ substituent groups mayoptionally be protected by a protecting group.

[0203] One embodiment of the compounds of formula (XII) are thosewherein:

[0204] R is H or C₁₋₃alkyl; and

[0205] R₅ is selected from H, C₁₋₃alkyl branched or unbranched, C₃₋₈cycloalkyl, C₅₋₇cycloalkenyl or C₂₋₄ alkenyl, each being optionallysubstituted with one or more OH, CN, NR₈R₉, CONR₈R₉, C₃₋₈- cycloalkyl,C₅₋₇cycloalkenyl, phenyl, heteroaryl or heterocycle; wherein eachphenyl, heteroaryl or heterocycle is optionally substituted with one ormore C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CN, NO₂, amidino, guanidino,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one or more of the aminonitrogens in the amidino or guanidino groups in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl, C₁₋₃alkoxy orCO₂R₁₀;

[0206] or R₅ is selected from CO₂R₁₀, NR₈R₉, CONR₈R₉, phenyl, furyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl,benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl, or indolyl-CO—,wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, benzofuranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl,pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl orindolyl-CO— is optionally substituted with one to three:

[0207] halogen, NO₂, S(O)_(p)NR₈R₉, C₀₋₃alkylS(O)_(p), NR₈R₉,(CH₂)_(n)CO₂R₁₀, ureido, guanidino, cycloalkyl, phenyl, heteroaryl,heterocycle, cycloalkyl-Z-, phenyl-Z-, heteroaryl-Z-, heterocycle-Z-, orC₁₋₃alkyl optionally substituted with phenyl or NR₈R₉, wherein Z is abridging group selected from C₁₋₃ alkylene branched or unbranched, O,S(O)_(p) or NH, and wherein each cycloalkyl, phenyl, heteroaryl orheterocycle is optionally substituted with NO₂, C₁₋₃alkyl, C₁₋₃alkoxy,CO₂R₁₀, (CH₂)_(n)NR₈R₉, O(CH₂)₂₋₄NR₈R₉ or guanidino, wherein one or moreof the amino nitrogens in the guanidino group in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy;and wherein each alkyl, alkoxy and phenyl in this paragraph isoptionally partially or fully halogenated;

[0208] or R₅ is a C₆₋₇ bridged-bicyclic ring system, optionally havingone or two double bonds in the ring system, and wherein up to 1 carbonatom in the ring system may be replaced by a nitrogen atom; and whereinsaid ring system may be optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, halogen, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉;

[0209] Yet another embodiment of the compounds of formula (XII) arethose described immediately above, wherein:

[0210] R₅ is selected from C₂₋₄ alkenyl, C₃₋₈ cycloalkyl orC₅₋₇cycloalkenyl, each being optionally substituted with one or more OH,CN, NR₈R₉, CONR₈R₉ or phenyl; wherein phenyl is optionally substitutedwith one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen, amidino, guanidino,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one or more of the aminonitrogens in the amidino or guanidino groups in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy;

[0211] or R₅ is selected from phenyl, furyl, thienyl, oxazolyl,thiazolyl , pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl,pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl orindolyl-CO—, wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl,pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-CO— isoptionally substituted with one to two:

[0212] halogen, NO₂, SO₂NR₈R₉, NR₈R₉, (CH₂)_(n)CO₂R₁₀, ureido,cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Z-,heteroaryl-Z- or heterocycle-Z-, or C₁₋₃alkyl optionally substitutedwith NR₈R₉, wherein Z is a bridging group selected from C₁₋₃ alkylenebranched or unbranched or S(O)_(p), wherein each cycloalkyl, phenyl,heteroaryl or heterocycle is optionally substituted with NO₂, C₁₋₃alkyl,CO₂R₁₀, NR₈R₉ or guanidino, wherein one or more of the amino nitrogensin the guanidino group in this paragraph may be optionally substitutedwith C₁₋₃alkyl; and wherein each alkyl and phenyl in this paragraph isoptionally partially or fully halogenated;

[0213] or R₅ is a 7-azabicyclo[2.2.1]heptane ring system, optionallyhaving one or two double bonds in the ring system, wherein said ringsystem may be optionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy,halogen, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉;

Formula (XVIII)

[0214] In their broadest generic aspect, intermediate compounds of theformula (XVIII) are represented by the following formula:

[0215] wherein:

[0216] Ar₁ is an aromatic or nonaromatic carbocycle, heteroaryl orheterocycle; wherein said carbocycle, heteroaryl or heterocycle isoptionally substituted by one or more R₁, R₂ and R₃;

[0217] R is H, C₁₋₃alkyl or cyclopropyl;

[0218] R₁ and R₂ are the same or different and are selected from H,halogen, CN, NO₂, C₁₋₁₀ branched or unbranched saturated or unsaturatedalkyl, C₁₋₁₀ branched or unbranched alkoxy, C₁₋₁₀ branched or unbranchedacyl, C₁₋₁₀ branched or unbranched acyloxy, C₁₋₁₀ branched or unbranchedalkylthio, aminosulfonyl, di-(C₁₋₃)alkylaminosulfonyl, NR₈R₉, aryl,aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein theabovementioned R₁ and R₂ are optionally partially or fully halogenatedor optionally substituted with one to three groups independentlyselected from the group consisting of oxo, OH, NR₈R₉, C₁₋₆ branched orunbranched alkyl, C₃₋₇cycloalkyl, phenyl, naphthyl, heteroaryl,aminocarbonyl and mono- or di(C₁₋₃)alkylaminocarbonyl;

[0219] R₃ is selected from the group consisting of H, halogen, OH,(CH₂)_(n)NR₈R₉, (CH₂)_(n)CO₂R₁₀, C₁₋₃alkyl optionally substituted withOH, C₁₋₃ alkoxy optionally halogenated and C₁₋₃ alkylthio;

[0220] R₄ is selected from H, C₁₋₆ alkyl branched or unbranched,saturated or unsaturated, and optionally substituted with phenyl, OH orC₁₋₃alkoxy, C₃₋₁₀-cycloalkyl, or C₅₋₈cycloalkenyl; or R₄ is selectedfrom (CH₂)_(m)NR₈R₉, (CH₂)_(m)NR₈COR₁₀, (CH₂)_(n)CO₂R₁₀,(CH₂)_(n)CONR₈R₉, phenyl, heteroaryl or heterocycle, each phenyl ,heteroaryl or heterocycle being optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, (CH₂)_(m)NR₈R₉, OH, SO₃H or halogen;

[0221] R₈ and R₉ are the same or different and are each independentlyselected from H, OH, CO₂R₁₀, C₁₋₁₀ acyl branched or unbranched,C₁₋₃alkoxy, C₁₋₆alkyl branched or unbranched,C₃₋₆alkenyl,C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl, heteroaryl orheterocycle; wherein said alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl,heteroaryl or heterocycle are optionally substituted with OH,C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl orheteroaryl;

[0222] or R₈ and R₉ together form a 3-7 member alkylene chain completinga ring about the N atom to which they are attached; wherein saidalklylene chain is optionally interrupted by O, S(O)_(p), NCOR₁₀,NCO₂R₁₀, NR₁₁ or NC(═NR₁₁)NR₁₁R₁₂; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₁R₁₂;

[0223] R₁₀ is selected from H, C₁₋₆alkyl, C₃₋₈cycloalkyl, wherein eachalkyl or cycloalkyl is optionally substituted with phenyl, OH,C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂, or R₁₀ is phenyl optionallysubstituted with one to three C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(m)NR₈R₉, (CH₂)_(n)CONR₈R₉ or O(CH₂)₂₋₄NR₈R₉;

[0224] R₁₁ and R₁₂ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0225] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂;

[0226] m is 1-4;

[0227] n is 0-3;

[0228] and p is 0-2;

[0229] wherein one or more of the primary amine or secondary aminenitrogen atoms in any of the R₄, R₅, R₆ and R₇ substituent groups mayoptionally be protected by a protecting group.

[0230] One embodiment of the compounds of formula (XVIII) are thosewherein:

[0231] Ar₁ is

[0232] a) a cycloalkyl group selected from cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl and cycloheptanyl;

[0233] b) a cycloalkenyl group selected from cyclopentenyl,cyclohexenyl, and cycloheptenyl;

[0234] c) an aromatic carbocycle selected from phenyl, naphthyl,indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl,

[0235] d) a heteroaryl selected from pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl,or a fusedheteroaryl selected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine,cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine,cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline,cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole,cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or

[0236] e) a heterocycle selected from: pyrrolinyl, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,pyranyl, thiopyranyl, piperazinyl and indolinyl;

[0237] wherein each of the above Ar₁ are optionally substituted by oneor more R₁, R₂ and R₃;

[0238] R₁ and R₂ are as defined in claim 1, and R₃ is hydrogen, halogen,methyl, methoxy, hydroxymethyl or OH; and

[0239] R₄ is H, C₁₋₃alkyl branched or unbranched, saturated orunsaturated, and optionally substituted with OH; or R₄ is (CH₂)₂₋₃NR₈R₉,(CH₂)_(n)CO₂R₁₀ or (CH₂)_(n)CONR₈R₉;

[0240] R₈ and R₉ are the same or different and are each independentlyselected from H, OH, C₁₋₃alkyl branched or unbranched, CO₂R₁₀ ,C₃₋₈cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl or heterocycle;wherein said alkyl, cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl orheterocycle are optionally substituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy,CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl or heteroaryl;

[0241] or R₈ and R₉ together form a 4-6 member alkylene chain completinga ring about the N atom to which they are attached; wherein saidalkylene chain is optionally interrupted by NCO₂R₁₀ or NR₁₁; and whereinsaid ring is optionally substituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or—(CH₂)_(n)NR₁₁R₁₂;

[0242] R₁₀ is H or C₁₋₆alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy or NR₁₁R₁₂;

[0243] R₁₁ and R₁₂ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0244] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂; and

[0245] n is 0-3.

[0246] Yet another embodiment of the compounds of formula (XVIII) arethose described immediately above, wherein:

[0247] Ar₁ is phenyl or pyridyl, each optionally substituted by one ormore R₁, R₂ and R₃;

[0248] R is H or C₁₋₃alkyl;

[0249] R₁ and R₂ are the same or different and selected from: halogen,C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally partially or fullyhalogenated, NO₂ or NR₈R₉;

[0250] R₃ is H, halogen, methyl or methoxy;

[0251] R₄ is H, C₁₋₃alkyl branched or unbranched, saturated orunsaturated, and optionally substituted with OH; or R₄ is (CH₂)₂₋₃NR₈R₉or CO₂R₁₀;

[0252] R₈ and R₉ are the same or different and are each independentlyselected from H, C₁₋₃alkyl branched or unbranched, CO₂R₁₀, phenyl, orbenzoyl; wherein said alkyl, phenyl or benzoyl are optionallysubstituted with OH or C₁₋₃alkoxy;

[0253] or R₈ and R₉ together form a —(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂— group or a—(CH₂)₂—N(R₁₁)—(CH₂)₂— group; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, or OH;

[0254] R₁₀ is H or C₁₋₃alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy or NR₁₁R₁₂;

[0255] R₁₁ and R₁₂ are each independently selected from H and C₁₋₃ alkyloptionally substituted with C₁₋₃alkoxy or OH;

[0256] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂.

Formula (XIX)

[0257] In their broadest generic aspect, intermediate compounds offormula (XIX) are represented by the following formula:

[0258] wherein:

[0259] Ar₁ is an aromatic or nonaromatic carbocycle, heteroaryl orheterocycle; wherein said carbocycle, heteroaryl or heterocycle isoptionally substituted by one or more R₁, R₂ and R₃;

[0260] R is H, C₁₋₃alkyl or cyclopropyl

[0261] R₁ and R₂ are the same or different and are selected from H,halogen, CN, NO₂, C₁₋₁₀ branched or unbranched saturated or unsaturatedalkyl, C₁₋₁₀ branched or unbranched alkoxy, C-₁₋₁₀ branched orunbranched acyl, C₁₋₁₀ branched or unbranched acyloxy, C₁₋₁₀ branched orunbranched alkylthio, aminosulfonyl, di-(C₁₋₃)alkylaminosulfonyl, NR₈R₉,aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy;wherein the abovementioned R₁ and R₂ are optionally partially or fullyhalogenated or optionally substituted with one to three groupsindependently selected from the group consisting of oxo, OH, NR₈R₉, C₁₋₆branched or unbranched alkyl, C₃₋₇cycloalkyl, phenyl, naphthyl,heteroaryl, aminocarbonyl and mono- or di(C₁₋₃)alkylaminocarbonyl;

[0262] R₃ is selected from the group consisting of H, halogen, OH,(CH₂)_(n)NR₈R₉, (CH₂)_(n)CO₂R₁₀, C₁₋₃alkyl optionally substituted withOH, C₁₋₃ alkoxy optionally halogenated and C₁₋₃ alkylthio;

[0263] R₄ is selected from H, C₁₋₆ alkyl branched or unbranched,saturated or unsaturated, and optionally substituted with phenyl, OH orC₁₋₃alkoxy, C₃₋₁₀-cycloalkyl, or C₅₋₈cycloalkenyl; or R₄ is selectedfrom (CH₂)_(m)NR₈R₉, (CH₂)_(m)NR₈COR₁₀, (CH₂)_(n)CO₂R₁₀,(CH₂)_(n)CONR₈R₉, phenyl, heteroaryl or heterocycle, each phenyl ,heteroaryl or heterocycle being optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, (CH₂)_(m)NR₈R₉, OH, SO₃H or halogen;

[0264] R₈ and R₉ are the same or different and are each independentlyselected from H, OH, CO₂R₁₀, C₁₋₁₀ acyl branched or unbranched,C₁₋₃alkoxy, C₁₋₆alkyl branched or unbranched,C₃₋₆alkenyl,C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl, heteroaryl orheterocycle; wherein said alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl,heteroaryl or heterocycle are optionally substituted with OH,C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl orheteroaryl;

[0265] or R₈ and R₉ together form a 3-7 member alkylene chain completinga ring about the N atom to which they are attached; wherein saidalkylene chain is optionally interrupted by O, S(O)_(p), NCOR₁₀,NCO₂R₁₀, NR₁₁ or NC(═NR₁₁)NR₁₁R₁₂; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₁R₁₂;

[0266] R₁₀ is selected from H, C₁₋₆alkyl, C₃₋₈cycloalkyl, wherein eachalkyl or cycloalkyl is optionally substituted with phenyl, OH,C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂, or R₁₀ is phenyl optionallysubstituted with one to three C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(m)NR₈R₉, (CH₂)_(n)CONR₈R₉ or O(CH₂)₂₋₄NR₈R₉;

[0267] R₁₁ and R₁₂ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0268] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂;

[0269] m is 1-4;

[0270] n is 0-3;

[0271] and p is 0-2;

[0272] wherein one or more of the primary amine or secondary aminenitrogen atoms in any of the R₄, R₅, R₆ and R₇ substituent groups mayoptionally be protected by a protecting group.

[0273] One embodiment of the compounds of formula (XIX) above iswherein:

[0274] Ar₁ is

[0275] a) a cycloalkyl group selected from cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl and cycloheptanyl;

[0276] b) a cycloalkenyl group selected from cyclopentenyl,cyclohexenyl, and cycloheptenyl;

[0277] c) an aromatic carbocycle selected from phenyl, naphthyl,indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl,

[0278] d) a heteroaryl selected from pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl,or a fusedheteroaryl selected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine,cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine,cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline,cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole,cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or

[0279] e) a heterocycle selected from: pyrrolinyl, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,pyranyl, thiopyranyl, piperazinyl and indolinyl;

[0280] wherein each of the above Ar₁ are optionally substituted by oneor more R₁, R₂ and R₃;

[0281] R₁ and R₂ are as defined in claim 1, and R₃ is hydrogen, halogen,methyl, methoxy, hydroxymethyl or OH; and

[0282] R₄ is H, C₁₋₃alkyl branched or unbranched, saturated orunsaturated, and optionally substituted with OH; or R₄ is (CH₂)₂₋₃NR₈R₉,(CH₂)_(n)CO₂R₁₀ or (CH₂)_(n)CONR₈R₉;

[0283] R₈ and R₉ are the same or different and are each independentlyselected from H, OH, C₁₋₃alkyl branched or unbranched, CO₂R₁₀,C₃₋₈cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl or heterocycle;wherein said alkyl, cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl orheterocycle are optionally substituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy,CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl or heteroaryl;

[0284] or R₈ and R₉ together form a 4-6 member alkylene chain completinga ring about the N atom to which they are attached; wherein saidalkylene chain is optionally interrupted by NCO₂R₁₀ or NR₁₁; and whereinsaid ring is optionally substituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or—(CH₂)_(n)NR₁₁R₁₂;

[0285] R₁₀ is H or C₁₋₆alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy or NR₁₁R₁₂;

[0286] R₁₁ and R₁₂ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0287] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂; and

[0288] n is 0-3.

[0289] Yet another embodiment of the compounds of formula (XIX) arethose described immediately above, wherein:

[0290] Ar₁ is phenyl or pyridyl, each optionally substituted by one ormore R₁, R₂ and R₃;

[0291] R is H or C₁₋₃alkyl;

[0292] R₁ and R₂ are the same or different and selected from: halogen,C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally partially or fullyhalogenated, NO₂ or NR₈R₉;

[0293] R₃ is H, halogen, methyl or methoxy;

[0294] R₄ is H, C₁₋₃alkyl branched or unbranched, saturated orunsaturated, and optionally substituted with OH; or R₄ is (CH₂)₂₋₃NR₈R₉or CO₂R₁₀;

[0295] R₈ and R₉ are the same or different and are each independentlyselected from H, C₁₋₃alkyl branched or unbranched, CO₂R₁₀, phenyl, orbenzoyl; wherein said alkyl, phenyl or benzoyl are optionallysubstituted with OH or C₁₋₃alkoxy;

[0296] or R₈ and R₉ together form a —(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂— group or a—(CH₂)₂—N(R₁₁)—(CH₂)₂— group; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, or OH;

[0297] R₁₀ is H or C₁₋₃alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy or NR₁₁R₁₂;

[0298] R₁₁ and R₁₂ are each independently selected from H and C₁₋₃ alkyloptionally substituted with C₁₋₃alkoxy or OH;

[0299] or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂.

[0300] In a further embodiment of the invention, there are provided thefollowing compounds of the formula (I):

[0301]2-(2,6-Dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0302]2-(2,6-Dichlorophenylamino)-7-furan-2-yl-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0303]2-(2,6-Dichlorophenylamino)-1-methyl-7-phenyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0304]2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-nitrophenyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0305]7-(3-Aminophenyl)-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0306]1-{3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-phenyl}-3-ethylurea;

[0307]2-(2,6-Dichlorophenylamino)-1-methyl-7-vinyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0308]2-(2,6-Dichlorophenylamino)-1-methyl-7-thiophen-2-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0309]2-(2,6-Dichlorophenylamino)-1-methyl-7-[2-(3-nitrophenyl)thiazol-4-yl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0310]2-(2,6-Dichlorophenylamino)-7-imidazol-2-yl-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0311]2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-phenyloxazol-5-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0312]2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazoline-7-carboxamide;

[0313]2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-methylpropen-1-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0314]2-(2,6-Dichlorophenylamino)-1-methyl-7-pyridin-2-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0315] 2-(2,6-Dichlorophenylamino)-1-methyl-7-pyridin-3-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0316]2-(2,6-Dichlorophenylamino)-1-methyl-1H-imidazo[4,5-f]quinazoline-7,9-6H,8H-dione;

[0317]2-(2,6-Dichlorophenylamino)-1-methyl-7-propen-2-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0318]7-Cyclopent-1-enyl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0319]7-[2-(3-Aminophenyl)-thiazol-4-yl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0320] Ethyl 2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazoline-7-carboxylate;

[0321]7-Benzofuran-2yl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0322]2-(2,6-Dichlorophenylamino)-1-methyl-7-(1-methylprop-1-enyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0323]2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-methyloxazol-5-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0324]2-(2,6-Dichlorophenylamino)-7-(1H-indole-3-carbonyl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0325]2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-piperazin-1-yl-cyclopent-1-enyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0326]7-Cyclohex-1-enyl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0327]2-(2,6-Dichlorophenylamino)-1-methyl-7-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0328]2-(2,6-Dichlorophenylamino)-1-methyl-7-[5-(2-nitrophenyl)-furan-2-yl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0329]2-(2,6-Dichlorophenylamino)-7-furan-3-yl-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0330]7-(5-Bromofuran-2-yl)-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0331]2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-methylfuran-2-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0332]7-Cyclopropyl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0333]2-(2,6-Dichlorophenylamino)-1-methyl-7-[3-(4-methylpiperazine-1-sulfonyl)-phenyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0334]4-{3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-cyclopent-2-enyl}-piperazine-1-carboxylicacid tert-butyl ester;

[0335]2-(2,6-Dichlorophenylamino)-7-(3-hydroxycyclopent-1-enyl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0336]2-(2,6-Dichlorophenylamino)-1-methyl-7-[3-(piperazine-1-sulfonyl)-phenyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0337] 3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-cyclopent-3-enecarbonitrile;

[0338]7-Amino-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0339]3-{2-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-propenyl}-benzonitrile;

[0340]3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-cyclopent-3-enecarboxamide;

[0341] 2-{4-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-thiazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester;

[0342]2-(2,6-Dichlorophenylamino)-1-methyl-7-[1-methyl-2-(3-nitrophenyl)-vinyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0343] 3-{4-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-thiazol-2-ylmethyl}-piperidine-1-carboxylicacid benzyl ester;

[0344]7-[2-(2-Aminocyclohexyl)-thiazol-4-yl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0345]2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-piperidin-3-ylmethyl-thiazol-4-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0346]2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-methylthiazol-4-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0347]2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-oxocyclopent-1-enyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0348] 3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-2,5-dihydro-pyrrole-1-carboxylicacid tert-butyl ester;

[0349]7-[2-(3-Aminophenyl)-1-methylvinyl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0350] Acetic acid2-(4-{3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-benzenesulfonyl}-piperazin-1-yl)-2-oxoethyl ester;

[0351]2-(2,6-Dichlorophenylamino)-7-(2,5-dihydro-1H-pyrrol-3-yl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0352]7-[2-(3-Aminomethylphenyl)-1-methylvinyl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0353]4-{3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-benzenesulfonyl}-piperazine-1-carboxamidine;

[0354]2-(2,6-Dichlorophenylamino)-7-{3-[4-(2-hydroxyacetyl)-piperazine-1-sulfonyl]-phenyl}-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0355]3-{2-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-propenyl}-benzamidine;

[0356]7-(7-Azabicyclo[2.2.1]hepta-2,5-dien-2-yl)-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0357]5-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester;

[0358]2-(2,6-Dichlorophenylamino)-7-(1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrol-5-yl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0359]2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-pyrrolidin-2yl-thiazol-4-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;

[0360]7-[2-(3,5-Diaminophenyl)-1-methylvinyl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;and

[0361]2-(2,6-Dichlorophenylamino)-1-methyl-7-[4-(piperazine-1-sulfonyl)-phenyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;and

[0362] the pharmacuetically acceptable derivatives thereof.

[0363] Any compounds of this invention containing one or more asymmetriccarbon atoms may occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. Each stereogenic carbon may be in the R or Sconfiguration, or a combination of configurations.

[0364] Some of the compounds of the invention can exist in more than onetautomeric form. The invention includes all such tautomers.

[0365] The compounds of the invention are only those which arecontemplated to be ‘chemically stable’ as will be appreciated by thoseskilled in the art. For example, a compound which would have a ‘danglingvalency’, or a ‘carbanion’ are not compounds contemplated by theinvention.

[0366] All terms as used herein in this specification, unless otherwisestated, shall be understood in their ordinary meaning as known in theart. For example, “C₁₋₆alkoxy” is a C₁₋₆alkyl with a terminal oxygen,such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl,alkylene or alkynyl groups shall be understood as being branched orunbranched unless otherwise specified. Other more specific definitionsare as follows:

[0367] The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine.

[0368] The term “heteroaryl” refers to a stable 5-8 membered (butpreferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclicaromatic heterocycle radical. Each heterocycle consists of carbon atomsand from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. Theheterocycle may be attached by any atom of the cycle, which results inthe creation of a stable structure. Example “heteroaryl” radicalsinclude, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl,oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl,quinazolinyl and indazolyl,or a fused heteroaryl such ascyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine,cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine,cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline,cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline,cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole,cyclohexanobenzimidazole, cyclopentanobenzoxazole,cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole,cyclopentanothiophene and cyclohexanothiophene;

[0369] The term “heterocycle” refers to a stable 5-8 membered (butpreferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclicheterocycle radical which may be either saturated or unsaturated, and isnon-aromatic. Each heterocycle consists of carbon atoms and from 1 to 4heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle maybe attached to the main structure by any atom of the cycle, whichresults in the creation of a stable structure. Example “heterocycle”radicals include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,1,2,5,6-tetrahydropyridinyl, piperidinyl, morpholinyl, thiomorpholinyl,pyranyl, thiopyranyl, piperazinyl, indolinyl, and1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl.

[0370] As used herein and throughout this specification, the terms“nitrogen” and “sulfur” and their respective elements symbols includeany oxidized form of nitrogen and sulfur and the quaternized form of anybasic nitrogen.

[0371] The term “aryl” shall be understood to mean a 6-10 memberedaromatic carbocycle, “aryl” includes, for example, phenyl and naphthyl;other terms comprising “aryl” will have the same definition for the arylcomponent, examples of these moieties include: arylalkyl, aryloxy orarylthio.

[0372] The term “carbocycle” shall be understood to mean a 3-10 memberedaromatic or nonaromatic cyclic carbon chain. Examples of nonaromaticcarbocycles include cycloalkyl groups such as cyclopropyl, cyclobutyl,cyclopentyl; cycloalkylidene groups such as cyclopentylidene,cyclohexylidene; and cycloalkenyl groups such as cyclopentenyl,cyclohexenyl and cycloheptenyl. Examples of aromatic carbocycles includethe “aryl” compounds as described hereinabove.

[0373] The “C₆₋₁₂ bridged- or spiro-bicyclic ring system, optionallyhaving one or two double bonds in the ring system, and wherein up to 3carbon atoms in the ring system may be replaced by heteroatoms selectedfrom N, O and S” in the R₅ definition shall be understood to mean anyring system containing 6 to 12 carbon atoms and having at least onebridged-type or spiro-type fusion within the ring system, wherein up to3 of the aforementioned carbon atoms may optionally be replaced by aheteroatom independently selected from N, O and S. An example is aC₆₋₁₀-, preferably, C₆₋₇- bridged-bicyclic ring system, optionallyhaving one or two double bonds in the system, wherein up to 2,preferably up to 1, carbon atoms in the ring system are replaced by anitrogen atom. An example of such a ring system is7-azabicyclo[2.2.1]hept-2,5-diene. Other examples within the broaddefinition include norbornenyl, tropanyl, 1-azabicyclo[2.2.2]oct-2-enyl,7-azabicyclo[3.2.1]oct-6-enyl, spiro[4.5]dec-1-enyl, andspiro[4.4]non-1-enyl.

[0374] The term “acyl” shall be understood to mean an R—(C═O)— moietywherein R is an alkyl. Examples of R can be a C₁₋₁₀alkyl, saturated orunsaturated, branched or unbranched, or R can be “aryl” as definedhereinabove. An example when R is an aryl is the benzoyl group orC₆H₅—CO. “Acyloxy” shall be understood to mean an R—CO₂— group wherein Ris as defined in this paragraph.

[0375] As indicated above, one or more of the primary amine or secondaryamine nitrogen atoms in any of the R₄, R₅, R₆ and R₇ substituent groupsmay optionally be protected by a protecting group. Suitable protectinggroups for this purpose, for example, are those disclosed in T. W.Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”,Wiley, New York, 1990. Examples of suitable protecting groups for thispurpose include benzyloxycarbonyl, tert-butyloxycarbonyl,allyloxycarbonyl, acetyl and trifluoroacetyl. The invention includespharmaceutically acceptable derivatives of compounds of the invention. A“pharmaceutically acceptable derivative” refers to any pharmaceuticallyacceptable salt or ester of a compound of this invention, or any othercompound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound of this invention, apharmacologically active metabolite or pharmacologically active residuethereof.

[0376] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acidsinclude hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic,benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.Other acids, such as oxalic acid, while not themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of this invention and theirpharmaceutically acceptable acid addition salts. Salts derived fromappropriate bases include alkali metal (e.g., sodium), alkaline earthmetal (e.g., magnesium), ammonium and N—(C₁-C₄ alkyl)₄ ⁺ salts.

[0377] In addition, the compounds of this invention include prodrugs ofcompounds of the invention. Prodrugs include those compounds that, uponsimple chemical transformation, are modified to produce a compound ofthe invention. Simple chemical transformations include hydrolysis,oxidation and reduction, enzymatically, metabolically or otherwise.Specifically, when a prodrug of this invention is administered to apatient, the prodrug may be transformed into a compound of theinvention, thereby imparting the desired pharmacological effect.

General Synthetic Methods

[0378] The compounds of the invention may be prepared by the methodsdescribed below. In each of the schemes below, the groups R₄, R₅, R₆,R₇, R₉ and Ar₁ are as defined above for general formula I except asnoted. Optimum reaction conditions and reaction times may vary dependingon the particular reactants used. Unless otherwise specified, solvents,temperatures, pressures and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Typically, reaction progressmay be monitored by thin layer chromatography (TLC) if desired.Intermediates and products may be purified by chromatography on silicagel and/or recrystallization. Starting materials and reagents are eithercommercially available or may be prepared by one skilled in the artusing methods described in the chemical literature.

[0379] Compounds of formula (I) in which Het is the dione shown informula (Ia) (Scheme 1) may be prepared as illustrated in Scheme 1 anddescribed below (Method A).

[0380] ** preliminary step II→Ia for when R₄ is not H

[0381] 6-Chloroanthranilic acid (II) is reacted with sodium cyanate inthe presence of a suitable acid, such as acetic acid, followed by asuitable base such as sodium hydroxide. Following an acidic work-up, thequinazolinedione III is isolated. In cases where R₄ is not H, one mayreact II (R₄═H) with an appropriate aldehyde (RCHO) in the presence of asuitable reducing agent, such as sodium borohydride to provide Ia(R₄═RCH₂).

[0382] Intermediate III is then subjected to nitration conditions, forexample treatment with nitric acid in the presence of sulfuric acid toprovide IV. Intermediate IV is then treated with excess amine RNH₂ (R═H,C₁₋₃ alkyl or cyclopropyl) in a suitable solvent, such as n-butanol,preferably in a sealed vessel with heating at about 50 to 150° C., toprovide V.

[0383] Reduction of V, for example by treatment with hydrogen preferablyat 10-60 psi in the presence of a suitable catalyst such as 10% Pd/c,provides VI. Treatment of VI with the desired isothiocyanate (Ar₁NCS),in a suitable solvent such as DMF provides thiourea (VII). Cyclizationof VII may be accomplished by treatment with a suitable couplingreagent, such as dicyclohexylcarbodiimide or mercury oxide in a suitablesolvent such as THF or DMF to provide the desired compound Ia.

[0384] Compounds of formula (I) in which Het is substituted with R₅ asshown in formula (Ib) (Scheme 2) may be prepared as illustrated inScheme 2 and described below (Method B).

[0385] In cases where R₅ is H, one may treat 6-chloroanthranilic acid(II) with triazine in a suitable solvent, such as EtOH, in the presenceof a suitable base such as piperidine, preferably while heating at aboutthe reflux temperature of the solvent to provide the quinazolinone VIII(R₅═H). to obtain compounds where R₅ is not H, one may react the amideIX with an acid chloride R₅ COCl, in a suitable solvent, such as THF, inthe presence of a suitable base, such as triethylamine to provide anintermediate amide which is cyclized to VIII by treatment with asuitable base, for example sodium methoxide in methanol, preferably atreflux temperature. Intermediate VIII may then be converted to Ib by thesame general procedure described in Method A for a converting III to Ia.

[0386] The preparation of benzimidazole intermediates, which may be usedin alternate procedures to prepare compounds of formula (I) isillustrated in Scheme 3 and described below (Method C):

[0387] 2,6-Dichloro-3-nitrobenzonitrile (XIII) is treated with thedesired amine RNH₂ (R═H, C₁₋₃ alkyl or cyclopropyl) in a suitablesolvent such as THF or EtOAc to provide XIV. This intermediate is thentreated with R₄NH₂ in a suitable solvent such as EtOH, preferably in asealed vessel while heating at about 50-110° C. to provide XV. Reductionto XVI, formation of thiourea XVII and cyclization to benzimidazoleXVIII may be carried out as described for the conversion of V to Ia inMethod A. Hydrolysis of the nitrile, for example, by treatment withconcentrated H₂SO₄ at about 100° C., provides XIX.

[0388] Method D (Scheme 4) illustrates how one may prepare compounds offormula (Ib) from intermediate XVIII (R₄═H).

[0389] Treatment of XVIII (R₄═H) with an acid halide R₅COX (where X is ahalogen) or acid anhydride (R₅CO)₂O or with an acid R₅CO₂H and acoupling reagent such as dicyclohexylcarbodiimide or1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, in a suitable solvent,such as THF or DMF, in the presence of a suitable base such astriethylamine or 4-(dimethylamino)pyridine provides amide XX.

[0390] Hydrolysis of the nitrite, followed by cyclization to Ib may beachieved, for example, by treatment of XX with a suitable base, such asaqueous sodium hydroxide, and an oxidant such as hydrogen peroxide orsodium perborate in a suitable solvent such as dioxane.

[0391] Intermediate XIX (R₄═H) may be used to prepare compounds offormula (Ib) as outlined in Scheme 5 (Method E):

[0392] Formation of XXI may be accomplished as described above forconversion of XVIII to XX. Intermediate XXI may then by cyclized bytreatment with a suitable base such as sodium methoxide or potassiumt-butoxide in a suitable solvent such as MeOH or THF, respectively, atabout reflux temperature to provide Ib.

[0393] Intermediate XIX may also be used to prepare compounds of formula(Ia) as illustrated in Scheme 6 (Method F).

[0394] Treatment of XIX with carbonyldiimidazole (CDI) or a phosgeneequivalent in a suitable solvent such as THF provides Ia.

[0395] Compounds of formula (I) in which Het is partially saturated maybe prepared from intermediate XIX, as illustrated in Scheme 7 (MethodG).

[0396] Treatment of XIX with a ketone (R₆C(O)R₇, where R₆ and R₇ are notH) in the presence of a catalytic amount of an acid such as p-TsOH, in asuitable solvent such as THF provides Ic (R₆ and R₇ are not H). WhenR₄═H, the use of an aldehyde (R₅CHO) instead of a ketone provides Id.This compound may be oxidized to Ib by treatment with a suitableoxidizing agent such as MnO₂ or dichlorodicyanobenzoquinone.

[0397] Compounds of formula (Ib) where R₅═NHR₉, represented by formula(Ib′) below, may be prepared from intermediate XIX (where R₄═H) byMethod H as illustrated in Scheme 8.

[0398] Reaction of XIX with an isothiocyanate in a suitable solvent suchas DMF or THF provides thiourea XXII. Cyclization or XXII may beaccomplished by the addition of a suitable condensing agent such asmercury oxide to produce the desired product of formula (Ib′).

[0399] Scheme 9 (Method I) illustrates a procedure by which compounds offormula (I) with X═S may be prepared. Intermediate XXV may be preparedfrom XXIII by reaction with an acid chloride (R₅C(O)Cl) to form anintermediate amide, followed by cyclization by treating with a suitablebase such as sodium methoxide. Alternatively, if R₅═H one may react XXIVwith triazine in a suitable solvent such as EtOH, in the presence of asuitable base such as piperidine to produce XXV (R₅═H). Reduction of thenitro group to give XXVI and formation of thiourea XXVII may beaccomplished by procedures described in the above Methods. Cyclizationof XXVII to give I (X═S) may be achieved by treatment with bromine in asuitable solvent such as CHCl₃.

[0400] Several of these transformations are also exemplified below.

Methods of Therapeutic Use

[0401] The compounds of the invention are useful in inhibiting theactivity of src-family kinases and PDGFR kinase. In doing so, thecompounds are effective in blocking disease processes mediated by thesekinases. For example, by inhibiting p56 lck, the compounds blockdownstream signaling events following T cell activation by antigen.Activation of antigen-specific T cells is necessary for the inductionand progression of diseases, including autoimmune diseases, allergicdiseases and transplant rejection (J. H. Hanke et al., Inflamm. Res.,1995, 44, 357). Therefore the compounds of the invention are useful fortreating such diseases. These include but are not limited to rheumatoidarthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease,ulcerative colitis, psoriasis, graft versus host disease, systemic lupuserythematosus, insulin-dependent diabetes mellitus and asthma.

[0402] In view of their inhibitory effect on src-family kinases andPDGFR kinase, the compound of the invention are useful in treatingcancer. For example, the compounds of the invention are useful intreating src-dependent tumors, such as in mammary carcinoma, coloncarcinoma, melanoma and sarcoma, and are also useful in treatingPDGF-dependent tumors, such as ovarian cancer, prostate cancer andglioblastoma. In view of their inhibitory effect on src kinase, thecompounds of the invention are also useful in treating conditionsinvolving cerebral ischemia, for example, in reducing brain damagefollowing a stroke.

[0403] By inhibiting p60src, compounds of the invention may also beuseful in treating osteoporosis, Paget's disease, bone inflammation andjoint inflammation. By inhibiting PDGFR kinase, compounds of theinvention may also be useful in treating fibrotic diseases, restenosisand atherosclerosis. By inhibiting lyn kinase, the compounds of theinvention may also be useful in enhancing or potentiating theeffectiveness of radiation therapy.

[0404] For therapeutic use, the compounds of the invention may beadministered in any conventional dosage form in any conventional manner.Routes of administration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, rectally, topically or byinhalation. The preferred modes of administration are oral andintravenous. Compositions comprising the compounds of the invention foreach of the aforementioned routes of administration will be apparent tothe skilled artisan. For example, one embodiment of the inventionprovides for pharmaceutical compositions including a therapeuticallyeffective amount of the compounds according to the invention. Suchpharmaceutical compositions will include pharmaceutically acceptablecarriers and adjuvants as further described below.

[0405] The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutic compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. Advantageously, such combinationtherapies utilize lower dosages of the conventional therapeutics, thusavoiding possible toxicity and adverse side effects incurred when thoseagents are used as monotherapies. Compounds of the invention may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Advantageously, thecompounds may then be administered together in a single dosage form. Insome embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 5%, but more preferablyat least about 20%, of a compound of formula (I) (w/w) or a combinationthereof. The optimum percentage (w/w) of a compound of formula(I) mayvary and is within the purview of those skilled in the art.Alternatively, the compounds may be administered separately (eitherserially or in parallel). Separate dosing allows for greater flexibilityin the dosing regime.

[0406] As mentioned above, dosage forms of the compounds of thisinvention include pharmaceutically acceptable carriers and adjuvantsknown to those of ordinary skill in the art. These carriers andadjuvants include, for example, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 1-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. As theskilled artisan will appreciate, lower or higher doses may be requireddepending on particular factors. For instance, specific dosage andtreatment regimens will depend on factors such as the patient's generalhealth profile, the severity and course of the patient's disorder ordisposition thereto, and the judgment of the treating physician.

SYNTHETIC EXAMPLES Example 1 Synthesis of2-(2,6-Dichlorophenylamino)-1H-imidazo[4,5-f]quinazoline-7,9(6H,8H)-dione

[0407]

[0408] To a solution of 6-chloroanthranilic acid (1.72 g, 10 mmol) andNaOH (0.40 g, 10 mmol) in water (15 mL) was added sodium cyanate (0.72g, 11 mmol), followed by acetic acid (0.66 g, 11 mmol). The solution wasstirred for 9 h, and then acidified with conc. HCl. The precipitate wasfiltered off and washed with water. The wet solid was added to asolution of NaOH (8.0 g, 200 mmol) in water (60 mL) and stirred for 20h. The precipitate was filtered off and suspended in water (80 mL), thenheated to boiling and acidified with 50% H₂SO₄. The cooled mixture wasfiltered, the solid washed well with water and dried to give5-chloroquinazolin-2,4-dione (1.42 g, 72%).

[0409] A solution of the above quinazolinedione (0.98 g, 5.0 mmol) inconc. H₂SO₄ (5 mL) was cooled to −10° C., and 90% HNO₃ (0.35 g, 5.0mmol) was added with stirring. Stirring continued for 1 h at −10° C.,and 1.5 h at room temperature. The mixture was poured onto ice,filtered, washed with water and dried to give5-chloro-6-nitroquinazolin-2,4-dione, along with some of the 8-nitroisomer (1.3 g, 94%).

[0410] Butanol (10 mL) was saturated with ammonia and placed in a sealedtube with the above compound (1.0 g, 4.1 mmol). The tube was heated to125° C. for 3 h, then cooled. The solid was collected, washed withwater, then ether, and dried to give 5-amino-6-nitroquinazolin-2,4-dione(0.82 g, 89%).

[0411] A suspension of the above amine (450 mg, 2.0 mmol) in DMF (15 mL)was hydrogenated over 10% Pd/C (60 mg) at 50 psi for 20 h. The catalystwas removed by filtration and the solvent removed to give5,6-diaminoquinazolin-2,4-dione (369 mg, 95%) as a dark solid.

[0412] A mixture of the above diamine (342 mg, 1.78 mmol) and2,6-dichlorophenyl-isothiocyanate (400 mg, 1.96 mmol) in DMF was stirredfor 17 h. The solvent was removed and the residue triturated with EtOActo give the thiourea. A portion of the thiourea (200 mg, 0.51 mmol) wasdissolved in DMF (2 mL) and a solution of dicyclohexylcarbodiimide (125mg, 0.61 mmol) in THF (4 mL) was added. The mixture was heated to 80° C.under reflux for 7 h, and the solvent removed. The residue was dissolvedin CH₂Cl₂/THF/TFA (150:50:1) and filtered though a plug of silica. Thefiltrate was evaporated, the residue triturated twice with THF, and thesupernatant pipetted off. The solid was suspended in MeOH, neutralizedwith NH₄OH, and the product collected by centrifugation to give thetitle compound, 1 (89 mg). Mp>300° C.

Example 2 Synthesis of2-(2,6-Dichlorophenylamino)-6-methyl-1H-imidazo[4,5-f]quinazoline-7,9(6H,8H)-dione

[0413]

[0414] Sodium (3.35 g, 146 mmol) was slowly added to stirred MeOH (45mL). Upon completion of gas evolution, 6-chloroanthranilic acid (5 g, 29mmol) was added forming a suspension. This mixture was added to aseparate flask containing a suspension of paraformaldehyde (1.22 g, 43.5mmol) in MeOH (35 mL), and the resulting solution was stirred for 5 h atroom temperature. Sodium borohydride (1.1 g, 29 mmol) was added and themixture refluxed for 3 h. The cooled mixture was hydrolyzed with 1 Mpotassium hydroxide then neutralized to pH 3 using 2 M HCl. Theprecipitate was filtered to yield 2-chloro-6-methylamino benzoic acid(2.2 g, 41%).

[0415] 2-Chloro-6-methylamino benzoic acid was converted to5-amino-1-methyl-6-nitroquinazolin-2,4-dione by the three step proceduredescribed in Example 1.

[0416] A suspension of 5-amino-1-methyl-6-nitroquinazolin-2,4-dione (400mg, 1.64 mmol) in MeOH (70 mL) was hydrogenated over 10% Pd/C (150 mg)in a Parr shaker at 50 psi until uptake ceased. The catalyst was removedby filtration and the filtrate concentrated to yield5,6-diamino-1-methylquinazolin-2,4-dione (350 mg, 99% crude).

[0417] A solution of the above diamine (350 mg, 1.69 mmol) and2,6-dichlorophenylisothiocyanate (381 mg, 1.88 mmol) in DMF (15 mL) wasstirred under nitrogen for 72 hr. The solvent was evaporated and theresidue triturated with ethyl acetate to yield the thiourea (430 mg,62%). A portion of the thiourea (300 mg, 0.73 mmol) was dissolved in DMF(3 mL) and a solution of dicyclohexylcarbodiimide (166 mg, 0.8 mmol) inTHF (6 mL) was added. The mixture was stirred at 80° C. for 4 h. Thesolvent was removed, and the residue crystallized twice from MeOH toyield the title compound, 2 (65 mg, 24%). Mp>300° C.

Example 3 Synthesis of2-(2,6-Dichlorophenylamino)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one

[0418]

[0419] A solution of 6-chloro anthranilic acid (2.12 g, 12.3 mmol) andtriazine (1.0 g, 12.3 mmol) in EtOH (40 mL) containing piperidine (3drops) was heated under reflux with stirring for 8 h. On coolingcrystals formed, which were filtered to yield 5-chloroquinazolin-4-one(1.55 g, 70%).

[0420] A solution of the above quinazolinone (1.26 g, 7.0 mmol) in conc.H₂SO₄ (7 mL) was cooled to −20° C., and 90% HNO₃ (0.49 g, 7.0 mmol) wasadded with stirring. Stirring continued for 1 h at −20° C., and 2 h atroom temperature. The mixture was poured onto ice, filtered, washed withwater and dried to give 5-chloro-6-nitroquinazolin-4-one, along with the8-nitro isomer in a 4:1 ratio. Three recrystallizations from EtOH gavethe product as a 6:1 ratio of isomers (0.85 g).

[0421] Butanol (20 mL) was saturated with ammonia and placed in a sealedtube with the above compound (800 mg, 3.6 mmol). The tube was heated to125° C. for 14 h, then cooled. The solid was collected, washed with EtOHand water, and dried to give 5-amino-6-nitroquinazolin-4-one (569 mg,78%).

[0422] A suspension of the above amine (250 mg, 1.21 mmol) in MeOH (50mL) was hydrogenated over 10% Pd/C (50 mg) at 50 psi for 5 h. Thecatalyst was removed by filtration and the filtrate concentrated toyield 5,6-diaminoquinazolin-4-one (210 mg, 98% crude).

[0423] A solution of the above diamine (205 mg, 1.19 mmol) and2,6-dichlorophenylisothiocyanate (272 mg, 1.3 mmol) in DMF (3 mL) wasstirred under nitrogen for 18 h. The solvent was evaporated and theresidue triturated with ethyl acetate to yield the thiourea (350 mg,77%). The thiourea was dissolved in DMF (4 mL) and a solution ofdicyclohexylcarbodiimide (228 mg, 1.1 mmol) in THF (8 mL) was added. Themixture was stirred at 80° C. for 8 h and the solvent evaporated. Theresidue was purified by column chromatography in CH₂Cl₂/MeOH 98:2-90:10.Pure fractions were combined, evaporated, and the residue recrystallizedfrom MeOH to give the title compound, 3 (87 mg). mp 230-235° C.

Example 4 Synthesis of2-(2,6-Dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one

[0424]

[0425] 5-Chloro-6-nitroquinazolin-4-one, from Example 3 (0.26 g, 1.15mmol) was suspended in MeOH (3 mL) at −20° C. Methylamine gas was passedinto the mixture for a few minutes, resulting in a clear solution. Thesolution was stirred at room temperature for 5 h and evaporated to give5-methylamino-6-nitroquinazolin-4-one in quantitative yield.

[0426] The above amine (350 mg, 1.6 mmol) was hydrogenated over platinumoxide (30 mg) in MeOH (200 mL) at 60 psi for 4 h. The mixture wasfiltered through diatomaceous earth and the solvent evaporated, to give6-amino-5-methylaminoquinazolin-4-one, which was immediately suspendedin EtOAc (20 mL) and THF (10 mL). A solution of2,6-dichlorophenylisothiocyanate (340 mg, 1.67 mmol) in EtOAc (5 mL) wasadded, and the mixture stirred for 16 h. The reaction mixture wasconcentrated to half the volume, filtered, and the solid washed withEtOAc to yield the thiourea (400 mg, 64% over 2 steps.)

[0427] A solution of the above thiourea (295 mg, 0.75 mmol) anddicyclohexylcarbodiimide (160 mg, 0.78 mmol) in THF (12 mL) and DMF (10mL) was heated to 70° C. with stirring for 48 h. The mixture was pouredinto ice water (50 mL) and filtered. The filtrate was extracted withEtOAc and evaporated. The residue was combined with the filtered solid,triturated with chloroform, and the supernatant decanted. The solid wasdissolved in boiling MeOH (100 mL), filtered hot, concentrated to 60 mL,and water (10 mL) added slowly. The crystals were collected to give thetitle compound, 4 (110 mg, 41%). Mp>300° C.

Example 5 Synthesis of2-(2,6-Dichlorophenylamino)-1-ethyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one

[0428] This compound was synthesized in by the method of Example 4.Mp>300° C.

Examples 6 and 7

[0429]

Example 6 Synthesis of2-(2,6-Dichlorophenylamino)-1,7-dimethyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one

[0430] A solution of 2,6-dichloro-3-nitrobenzonitrile (98.7 g, 0.455mol) in EtOAc (910 mL) was cooled to 5° C. 40% Aqueous methylamine (79.5mL, 1.14 mol) was added with vigorous mechanical stirring, keeping thetemperature at 10-15° C. After addition was complete, stirring wascontinued for 3 h at the same temperature. More methylamine (16 mL, 0.23mol) was added, and the mixture stirred for a further 1.5 h at roomtemperature. Water (300 mL) was added, followed by hexane (450 mL). Themixture was stirred for 15 min, filtered, and the solid washed withwater and MeOH, to give 6-chloro-2-methylamino-3-nitrobenzonitrile (80.3g, 83%), mp 167-170° C.

[0431] A suspension of the above amine (30.0 g, 142 mmol) in a 5.3 Msolution of ammonia in ethanol (200 mL) was heated in a sealed stainlesssteel reaction vessel (600 mL capacity) at 90° C. for 24 h. The reactionvessel was cooled to room temperature, then to 0° C., and opened. Theproduct was filtered, washed with ethanol (30 mL) and dried to give6-amino-2-methylamino-3-nitro-benzonitrile (25.94 g, 95%) as a yellowsolid.

[0432] A solution of the above diamine (5.0 g, 26 mmol) in THF (150 mL)was hydrogenated over 10% Pd/C (1.0 g) at 50 psi for 4 h. The reactionmixture was filtered through a pad of diatomaceous earth and rinsed withTHF (50 mL). The filtrate was not concentrated but used crude as a THFsolution.

[0433] To the above triamine solution was added2,6-dichlorophenylisothiocyanate (5.3 g, 26 mmol) and the solution wasstirred at room temperature for 0.5 hr. TLC indicated complete formationof the thiourea intermediate. Mercury (II) oxide (6.2 g, 29 mmol) wasthen added, and the mixture was heated to reflux for 2 h. TLC showedconversion to the benzimidazole. The reaction mixture was cooled to roomtemperature, activated carbon (about 1 g) was added, and stirred at 50°C. for 2 h. The mixture was filtered through a pad of diatomaceous earthand rinsed with EtOAc until the filtrate was colorless. The combinedfiltrates were concentrated to obtain a pink solid, which was trituratedwith EtOAc/hexane (1:4). The light grey color solid was filtered anddried to give5-amino-3-methyl-2-(2,6-dichlorophenylamino)-3H-benzimidazole-4-carbonitrile(7.42 g). The mother liquor was concentrated and triturated again toprovide a second crop (0.15 g), combined yield 87%, MS (EI⁺): MH⁺=331.

[0434] To the above amino nitrile (60 mg, 0.18 mmol) in THF (1 mL) wasadded acetic anhydride (74 mg, 0.72 mmol) and DMAP (1 crystal), and thesolution stirred for 22 h. MeOH (0.5 mL) was added, and stirringcontinued for 1 h. The solution was partitioned between EtOAc and diluteNH₄OH, and the residue from the organic layer purified by flashchromatography, eluting with CH₂Cl₂/THF 95:5, to give recovered aminonitrile (18 mg) and5-acetamido-3-methyl-2-(2,6-dichlorophenylamino)-3H-benzimidazole-4-carbonitrile(47 mg).

[0435] A suspension of the above acetamide (30 mg, 0.08 mmol) in dioxan(1 mL) and 0.2M NaOH (1 mL) was heated to 110° C. Urea-hydrogen peroxidecomplex (15 mg, 0.16 mmol) was added with stirring. Further 30 mgportions of urea-hydrogen peroxide were added at 2.5 h, 3.5 h and 21 h.After heating for 25 h, the mixture was cooled and partitioned betweenTHF and water. The residue from the organic layer was purified on aflash column, eluting with CH₂Cl₂/MeOH 98:2, to give the title compound,6 (7 mg, 23%), mp 305-310° C.(dec), MS (ES) 374, 376 (MH+).

Example 7 Synthesis of2-(2,6-Dichlorophenylamino)-1-methyl-7-phenyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one

[0436] A mixture of5-amino-3-methyl-2-(2,6-dichlorophenylamino)-3H-benzimidazole-4-carbonitrile(Example 6) (1 g, 3 mmol) and conc. H₂SO₄ (8 mL) was warmed to 100-110°C. for 1 h and monitored by TLC for the disappearance of startingmaterial. The mixture was cooled and poured onto a mixture of crushedice, sodium carbonate, and ether. The precipitate was filtered, washedwith water, dissolved in MeOH-methylene chloride, treated with carbon(decolorizing charcoal), dried (MgSO₄), filtered, and concentrated invacuo. The aqueous filtrate was washed with EtOAc (3×30 mL). Thecombined organic layers were washed with brine (25 mL), which was thenextracted with EtOAc (20 mL). The combined organic layers were dried(MgSO₄), filtered, and concentrated to yield 190 mg of a crude product.This was combined with the solid product and triturated withether-methylene chloride to afford5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzoimidazole-4-carboxylicacid amide (700 mg, 66%). The filtrate was chromatographed on silica gelto afford an additional 128 mg (12%) of product.

[0437] The above amino amide (50 mg, 0.15 mmol) was added to a solutionof benzoyl chloride (32 mg, 0.23 mmol) in THF (1 mL). Triethylamine(0.03 mL, 0.23 mmol) was added and the mixture stirred for 1 h. TLCshowed conversion to the benzamide. The solvent was evaporated and theresidue dissolved in MeOH (1 mL). Sodium methoxide in MeOH (25%, 0.2 mL)was added and the solution heated to reflux for 45 min. The cooledmixture was partitioned between 1M NH₄Cl and CH₂Cl₂. The residue fromthe organic layer was stirred and refluxed with MeOH (2 mL) for 1 h,cooled, filtered and washed with MeOH to yield the title compound, 7 (52mg, 79%) Mp>300° C. MS (ES+) 436, 438 (MH+).

Example 8 Synthesis of2-(2,6-Dichlorophenylamino)-1-methyl-7-furan-3-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one

[0438]

[0439] Furan-3 -carboxylic acid (20 mg, 0.18 mmol), hydroxybenzotriazole(24 mg, 0.18 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (35 mg, 0.18 mmol) were stirred together in DMF (1 mL) for15 min.5-Amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzoimidazole-4-carboxylicacid amide (Example 7)(50 mg, 0.15 mmol) was added, and stirringcontinued for 24 h. The solution was diluted with EtOAc and washed inturn with aqueous Na₂CO₃, water and brine. The organic layer wasevaporated and the residue dissolved in MeOH (2 mL). Sodium methoxide inMeOH (25%, 0.1 mL) was added and the solution heated to reflux for 45min. The cooled solution was partitioned between water and CH₂Cl₂. Theorganic layer was evaporated and the crude product stirred with MeOH (1mL) for 1 h. The solid was filtered, washed with a few drops of MeOH anddried to yield the title compound, 8 (14 mg, 22%). mp>300° C. MS (ES)428, 426 (MH+).

Example 9 Synthesis of7-allylamino-2-(2,6-dichlorophenylamino)-1-methyl--1,8-dihydro-9H-imidazo[4,5-]f]quinazoline-9-one

[0440]

[0441] A mixture of 100 mg (0.286 mmol) of5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylicacid amide (Example 7) and 114 mg (1.15 mmol) of allyl isothiocyanate inDMF was warmed at 45° C. for 48 h. The reaction was diluted with 30 mLof brine and extracted with four 15 mL portions of EtOAc. The combinedorganic layers were washed with five 15 mL portions of brine, dried(MgSO₄), filtered and concentrated in vacuo. The residue was adsorbedonto silica gel and chromatographed on silica gel (MeOH-methylenechloride, first 2:98, then 4:96, then 5:95) to afford 66 mg (51%) of2-(2,6-dichlorophenylamino)-3-methyl-5-(3-allyl-thioureido)-3H-benzimidazole-4-carboxylicacid amide.

[0442] A mixture of 66 mg (0.15 mmol) of the above amide and 300 mg(1.38 mmol) of mercury (II) oxide in THF was warmed at reflux for 18 h.The reaction was cooled to room temperature and filtered throughdiatomaceous earth. The filtrate was adsorbed onto silica gel andchromatographed over silica gel (methylene chloride, then MeOH-methylenechloride, first 1:99, then 2:98, then 3:97) to afford an off white solidwhich was triturated with methylene chloride-MeOH to afford 17 mg (27%)of the title compound 9, mp 255-260° C.

Example 10 Synthesis ofN-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-benzamide

[0443]

[0444] To a solution of 128 mg (0.36 mmol) of5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylicacid amide (Example 7) in 10 mL of THF was added 72 mg (0.45 mmol) ofbenzoyl isothiocyanate. The reaction was warmed at reflux and after 5min, thin-layer chromatography indicated a new product. 95 mg (0.44mmol) of mercury (II) oxide was added and refluxing continued for 24 h.The reaction was cooled and filtered through diatomaceous earth washingthe filter cake with EtOAc. The crude residue was adsorbed onto silicagel and chromatographed over silica gel (MeOH-methylene chloride, first1:99, then 2:98, then 3:97). The material from the column was trituratedwith ether-dichloromethane to afford 64 mg (36%) of the title compound10, mp, 185-190° C.

Example 11 Synthesis of7-amino-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazolin-9-one

[0445]

[0446] A mixture of 130 mg (0.27 mmol) 10 and 500 mg (3.62 mmol) ofpotassium carbonate in MeOH was stirred for 18 h. The mixture was thendiluted with brine and extracted with EtOAc to afford 12 mg of product.Additional material was obtained as an insoluble solid from theextraction layers. The combined materials were dissolved in 1N aqueousHCl, diluted with THF, made basic with solid/saturated aqueous sodiumbicarbonate and extracted with EtOAc to afford 40 mg (40%) of product.Trituration with ether gave 30 mg (30%) of title compound 11, mp>305° C.

Example 12 Synthesis of2-(2,6-Dichlorophenylamino)-1-methyl-7-(1-methyl-2-phenyl-vinyl)-1,6,7,8-tetrahydro-9H-imidazo[4,5-f]quinazolin-9-one

[0447]

[0448] A mixture of 110 mg (0.315 mmol) of5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylicacid amide, 184 mg (1.26 mmol) of α-methyl-trans-cinnamaldehyde and 60mg (0.31 mmol) of p-toluenesulfonic acid in 10 mL of THF were stirred atRT for 18 h. The reaction was made basic with saturated aqueous sodiumbicarbonate and extracted with EtOAc. The combined organic layers werewashed with saturated aqueous sodium bicarbonate, brine, dried (MgSO₄),filtered and evaporated in vacuo. The crude residue was chromatographedon silica gel to afford 102 mg (68%) of title compound 12.

Example 13 Synthesis of2-(2,6-Dichlorophenylamino)-1-methyl-7-(1-methyl-2-phenyl-vinyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one

[0449]

[0450] A mixture of 102 mg (0.213 mmol) 12 and 300 mg (3.45 mmol) ofmanganese dioxide was stirred in 15 mL of THF for 45 min. The reactionwas filtered through diatomaceous earth and evaporated in vacuo. Thecrude residue was evaporated onto silica gel and chromatographed oversilica gel (methylene chloride, then MeOH-methylene chloride first 1:99then 2:98). The material from the column was triturated withMeOH-methylene chloride to afford 70 mg (69%) of title compound 13,mp>305° C.

Example 14 Synthesis of2-(2,6-Dichlorophenylamino)-1-methyl-1H-imidazo[4,5-f]quinazoline-7,9(6H,8H)-dione

[0451]

[0452] To a solution of 80 mg (0.229 mmol) of5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylicacid amide (Example 7) in 8 mL THF cooled to 0° C. was added 67 mg (0.23mmol) of triphosgene. After stirring 30 min, the reaction was dilutedwith saturated aqueous sodium bicarbonate and water, and the THF wasevaporated in vacuo. The resulting suspension was filtered and the soliddried by pulling vacuum through the filter cake. The crude product wasabsorbed onto silica gel and chromatographed over silica gel(MeOH-methylene chloride first 1:99 then 2:98 then 3:97 then 4:96) toafford a solid which was triturated with methylene chloride to afford 20mg (23%) of the title compound 14, mp>300° C.

Example 15 Synthesis of2-(2,6-Dichlorophenylamino)-1,7-dimethyl-1,6,7,8-tetrahydro-9H-imidazo[4,5-f]quinazolin-9-one

[0453]

[0454] A mixture of 30 mg (0.086 mmol) of of5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylicacid amide (Example 7) and 1 mL (18 mmol) of acetaldehyde was stirredunder an argon atmosphere while chilled in an ice-water bath for 0.5 h,then warmed to room temperature. p-Toluenesulfonic acid was added,(catalytic) and after stirring for 1 h, 2 mL of MeOH was added. After 2h the reaction was poured into a mixture of saturated aqueous sodiumbicarbonate and EtOAc. The aqueous layer was extracted with EtOAc, thecombined organic layers were extracted with saturated aqueous sodiumbicarbonate, brine, dried (MgSO₄), treated with activated carbon,filtered, and concentrated in vacuo. The residue was chromatographedover silica gel, followed by elution on a TLC plate to yield 11 mg (34%)of title compound 15, mp 200-203° C.

Example 16 Synthesis of2-(2,6-Dichlorophenylamino)-1,7,7-trimethyl-1,6,7,8-tetrahydro-9H-imidazo[4,5-f]quinazolin-9-one

[0455]

[0456] A mixture of 38 mg (0.11 mmol) of5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylicacid amide (Example 7), 3 mg (0.02 mmol) p-toluenesulfonic acid, and 2mL (27 mmol) of acetone was stirred at room temperature for 1 h, thenheated to reflux for 1.5 h. The reaction was cooled and poured into amixture of saturated aqueous sodium bicarbonate and EtOAc. The aqueousphase was extracted with EtOAc, the combined organics were extractedwith saturated aqueous sodium bicarbonate, brine, dried (MgSO₄), treatedwith activated carbon, filtered, and concentrated in vacuo to afford 26mg of an orange solid. The crude product was chromatographed over silicagel to afford 20 mg (47%) of title compound 17, mp 238-239° C.

Example 17 Synthesis of2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-6,7,8,9-tetrahydro-1H-imidazol4,5-f]quinazoline-7-carboxylicacid ethyl ester

[0457]

[0458] A mixture of 100 mg (0.29 mmol) of5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylicacid amide (Example 7), 332 mg (2.9 mmol) of ethyl pyruvate, and acatalytic amount of p-toluenesulfonic acid in 2 mL of dichloromethanewas heated in a sealed tube to 85° C. for 2 h, then 0.5 mL EtOH wasadded, and heating continued for 15 min. The reaction was cooled andstirred at room temperature for 1 h. The reaction was concentrated invacuo, and the residue was suspended in dilute aqueous sodium hydroxide,filtered, washed with water and dried by pulling vacuum through thefilter cake. The crude product was purified on a TLC plate, andrecrystallized from EtOAc to afford 17.6 mg (13.5%) of title compound17, mp 245-247° C.

Additional Examples

[0459] The following additional compounds (Ex. Nos. 18 to 104) in thefollowing Table were prepared by methods analogous to those describedabove. Ex. No. Structure M. P. (° C.) 18

>300 19

200 (dec) 20

251 (dec) 21

278-284 (dec) 22

>300 23

280 24

>300 25

>300 26

>290 27

>300 28

>300 29

>300 30

>300 31

185-192 32

>300 33

>300 34

>250 (dec) 35

295 (dec) 36

240 (dec) 37

275-277 38

>300 39

>300 40

258 (dec) 41

265-268 42

>300 43

>300 44

45

278 (dec) 46

>300 47

>300 48

173-174 49

278 (dec) 50

283-284 51

52

295 (dec) 53

>300 54

255 55

289-292 56

>300 57

280-283 58

304-310 (dec) 59

>300 60

280 (dec) 61

215 (dec) 62

198-204 63

>300 64

257-260 65

168-170 66

285 67

189 68

210 69

>295 (dec) 70

288-290 71

290-292 72

>215 (dec) 73

209 74

254-256 75

163-169 76

155-160 77

295-300 (dec) 78

161-166 79

295 (dec) 80

310-313 81

>300 82

>275 (dec) 83

206-208 84

>300 (dec) 85

246 (dec) 86

240-241 (dec) 87

126-128 88

228-230 89

197-205 90

215 91

>300 92

>300 93

>300 94

210-215 95

265 (dec) 96

190 97

315-317 (dec) 98

290 99

195-200 (dec) 100

246 101

170 (dec) 102

284-288 103

>300 104

Assessment of Biological Properties Tyrosine Kinase Inhibition Assay

[0460] The inhibition of tyrosine kinases by the compounds of theinvention was measured with the following assay.

[0461] Kinase Reaction Buffer 50 mM Hepes, pH 7.5, 50 mM KCl, 25 mMMgCl₂, 5 mM MnCl₂, 100 μM, Na₃VO₄, 0.01% CHAPS, 1 mM DTT, and 50 mg/mLBSA, Adenosine 5′-Triphosphate (ATP) solution at 100 mM, pH 7.5-γ33P-ATP, 2000 Ci/mmol at 10 μCi/μl, -Poly(L-glutamic acid-L-tyrosine,4:1) or (E4Y)_(n) at 10 mg/mL in water.

[0462] Assay: Test compounds, obtained routinely at 5 mg/mL in 100% DMSOwere diluted appropriately into complete Kinase assay buffer with 10%DMSO, 10 μl of the 6× compound solution was distributed into each assaywell, the final compound concentration for IC₅₀ determinations rangedfrom 200 to 1 μg/mL. [γ33P]-ATP label was prepared as a 10 Ci/mmolworking solution in complete Kinase assay buffer. Protein kinase wasinitiated by adding 10 to 50 ηg of diluted enzyme stock.

[0463] Plates were incubated at 30° C. for 30 min. During the incubationperiod, the MultiScreen harvest plates were pre-wetted with 10% TCA/5%Ppi. 150 μl of TCA/PPi was added to all MultiScreen plate wells afterpre-wetting. The kinase reaction was stopped via replica transfer of thepolypropylene reaction wells into the MultiScreen plates. The plateswere incubated at room temperature for 5 min then vacuum harvested andwashed with 200 μl TCA/PPi 3-4 times per well, then 100 μl of cocktailper well was added.

[0464] Experimental data consisted of eight (8) compound doses induplicate with ten (10) enzyme control reaction wells (so-called totals)and six (6) background wells. The results are presented as PercentInhibition (Mean with S.D.) over the full compound dose range. IC₅₀potency estimates are determined using a floating inhibition maximum(Imax).

[0465] All compounds in the synthetic examples and Tables above wereevaluated in the tyrosine kinase assay above using p56 lck and werefound to have IC₅₀'s less than 10 μM.

[0466] Representative compounds from the examples above were evaluatedin the tyrosine kinase assay above using p60 src and were found to haveIC₅₀'s less than 10 μM.

[0467] Representative compounds from the examples above were evaluatedin the tyrosine kinase assay above using PDGFR kinase and were found tohave IC₅₀'s less than 10 μM.

[0468] Inhibition of IL-2 Production

[0469] Inactivation of T cells resulting from inhibition of the tyrosinekinase p56 lck can be measured by inhibition of IL-2 production inJurkat cells. 96-well flat bottom plates were coated with anti-CD3,clone UCHT1, (Immunotech cat. #1304) at 4 μg/ml in Phosphate BufferedSaline (PBS), 100 μl/well. The solution was prepared by taking 200 μl of200 μg/ml anti-CD3 stock/10 ml PBS. The plate was then incubated at 37°C. for 2 h. Jurkat cells were pelleted and counted. The cells wereresuspended at 2.5×10⁶ cells/ml in RPMI, 10% FBS (complete media). Testcompounds were diluted from a 5 mg/ml DMSO stock directly into completemedia.

[0470] 10 μl of 20×compound/well was added to a separate plate, followedby 100 μl of cell suspension in triplicate and this plate waspreincubated at 37° C. for 30 min. The 96-well plate containing anti-CD₃was aspirated, and the cells and compound transferred to this plate. 100μl of PMA (Phorbol 12-Myristate 13-Acetate, Sigma cat.#P-8139) at 20ng/ml was added, and the plate was incubated overnight at 37° C. (PMAstock at 1 mg/ml in ethanol, dilute 10 μl/ml in complete media, then 20μl/10 mls. in complete media. 100 μl/well=10 ng/ml. finalconcentration). The next day, the plate was centrifuged at 1500 rpm for5 min. at room temperature and the supernatants were removed. Thesupernatants were tested using R&D Systems Quantikine Human IL-2 Kit(cat.#2050). Samples were diluted 1:5 in RPMI1640, and 100 μl/well usedin the ELISA. The optical density of each well was determined using amicroplate reader set to 450 nm. EC₅₀ values were determined usingOrigin (non-linear regression) or SAS by plotting absorbance vs.concentration of compound.

[0471] Representatives from the synthetic examples and the Tables abovewere screened in this assay and had IC₅₀'s below 10 μM.

We claim:
 1. A compound of the following formula (I):

wherein: Ar₁ is an aromatic or nonaromatic carbocycle, heteroaryl orheterocycle; wherein said carbocycle, heteroaryl or heterocycle isoptionally substituted by one or more R₁, R₂ and R₃; X is NH,N—C₁₋₃alkyl, N-cyclopropyl, S or O; Y is NR₁₃; R₁ and R₂ are the same ordifferent and are selected from H, halogen, CN, NO₂, C₁₋₁₀ branched orunbranched saturated or unsaturated alkyl, C₁₋₁₀ branched or unbranchedalkoxy, C₁₋₁₀ branched or unbranched acyl, C₁₋₁₀ branched or unbranchedacyloxy, C₁₋₁₀ branched or unbranched alkylthio, aminosulfonyl,di-(C₁₋₃)alkylaminosulfonyl, NR₈R₉, aryl, aroyl, aryloxy, arylsulfonyl,heteroaryl and heteroaryloxy; wherein the abovementioned R₁ and R₂ areoptionally partially or fully halogenated or optionally substituted withone to three groups independently selected from the group consisting ofoxo, OH, NR₈R₉, C₁₋₆ branched or unbranched alkyl, C₃₋₇cycloalkyl,phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- ordi(C₁₋₃)alkylaminocarbonyl; R₃ is selected from the group consisting ofH, halogen, OH, (CH₂)_(n)NR₈R₉, (CH₂)_(n)CO₂R₁₀, C₁₋₃alkyl optionallysubstituted with OH, C₁₋₃ alkoxy optionally halogenated and C₁₋₃alkylthio; Het represents a fused heterocyclic ring having a formula A,B or C:

R₄ is selected from H, C₁₋₆ alkyl branched or unbranched, saturated orunsaturated, and optionally substituted with phenyl, OH or C₁₋₃alkoxy,C₃₋₁₀-cycloalkyl, or C₅₋₈cycloalkenyl; or R₄ is selected from(CH₂)_(m)NR₈R₉, (CH₂)_(m)NR₈COR₁₀, (CH₂)_(n)CO₂R₁₀, (CH₂)_(n)CONR₈ ₉,phenyl, heteroaryl or heterocycle, each phenyl , heteroaryl orheterocycle being optionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy,(CH₂)_(m)NR₈R₉, OH, SO₃H or halogen; R₅ is selected from H, C₁₋₁₀alkylbranched or unbranched, C₃₋₁₀ cycloalkyl, C₅₋₇cycloalkenyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆acyl, each being optionally substituted withone or more halogen, OH, oxo, CN, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₃alkoxy, NR₈R₉, ureido, guanidino, NR₈COR₁₀, SR₁₀, CONR₈R₉, CO₂R₁₀,C₃₋₁₀ cycloalkyl, C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl, aryloxy,arylthio, aryl, heteroaryl or heterocycle; wherein each of C₁₋₆alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkylidene,C₅₋₇cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle isoptionally substituted with one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen,CN, NO₂, amidino, guanidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; whereinone or more of the amino nitrogens in the ureido, amidino or guanidinogroups in this paragraph may be optionally substituted with C₁₋₃alkyl,phenylC₀₋₃alkyl, C₁₋₃alkoxy or CO₂R₁₀; or R₅ is selected from CO₂R₁₀,NR₈R₉, CONR₈R₉, aryl, heteroaryl, heterocycle, aryl-CO—, heteroaryl-CO—or heterocycle-CO—, wherein each aryl, heteroaryl or heterocycle isoptionally substituted with one to three: C₁₋₃alkoxy, halogen, NO₂, CN,S(O)_(p)NR₈R₉, C₀₋₃alkylS(O)_(p), NR₈R₉, (CH₂)_(n)CO₂R₁₀,(CH₂)_(n)CONR₈R₉, CO(CH₂)_(n)NR₈R₉, O(CH₂)₂₋₄NR₈R₉, ureido, guanidino,cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkyl-Z-, aryl-Z-,heteroaryl-Z-, heterocycle-Z-, or C₁₋₃alkyl optionally substituted withphenyl or NR₈R₉, wherein Z is a bridging group selected from C₁₋₁₀alkylene branched or unbranched, CO, S(O)_(p), O, S, NH, CONH, NHCO, COOor OOC, and wherein each cycloalkyl, aryl, heteroaryl or heterocycle isoptionally substituted with NO₂, C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CO₂R₁₀,(CH₂)_(n)NR₈R₉, O(CH₂)₂₋₄NR₈R₉, ureido or guanidino, wherein one or moreof the amino nitrogens in the ureido or guanidino groups in thisparagraph may be optionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkylor C-₁₋₃alkoxy; and wherein each alkyl, alkoxy and phenyl in thisparagraph is optionally partially or fully halogenated; or R₅ is a C6-12bridged- or spiro-bicyclic ring system, optionally having one or twodouble bonds in the ring system, and wherein up to 3 carbon atoms in thering system may be replaced by heteroatoms selected from N, O and S; andwherein said ring system may be optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, halogen, CO₂R₁₀, ureido, guanidino, amidino, (CH₂)_(n)NR₈R₉,or O(CH₂)₂₋₄NR₈R₉; wherein one or more of the amino nitrogens in theureido, guanidino or amidino groups in this paragraph may be optionallysubstituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy; R₆ isselected from H, C₁₋₆alkyl branched or unbranched, C₂₋₆ alkenyl branchedor unbranched, CO₂R₁₀, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, aryl,arylC₁₋₃alkyl, heteroaryl and heterocyclyl; wherein said C₁₋₆alkyl,C₂₋₆alkenyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, aryl, arylC₁₋₃alkyl,heteroaryl or heterocyclyl are optionally substituted with OH,C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl,heteroaryl or heterocyclyl; R₇ is H or C₁₋₆alkyl; R₈ and R₉ are the sameor different and are each independently selected from H, OH, CO₂R₁₀,C₁₋₁₀ acyl branched or unbranched, C₁₋₃alkoxy, C₁₋₆alkyl branched orunbranched, C₃₋₆alkenyl,C₃₋₈-cycloalkyl, aryl, arylC₁₋₃alkyl, aroyl,heteroaryl or heterocycle; wherein said alkyl, cycloalkyl, aryl,arylC₁₋₃alkyl, aroyl, heteroaryl or heterocycle are optionallysubstituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂,O(CH₂)₂₋₄NR₁₁R₁₂, aryl or heteroaryl; or R₈ and R₉ together form a 3-7member alkylene chain completing a ring about the N atom to which theyare attached; wherein said alkylene chain is optionally interrupted byO, S(O)_(p), NCOR₁₀, NCO₂R₁₀, NR₁₁ or NC(═NR₁₁)NR₁₁R₁₂; and wherein saidring is optionally substituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or—(CH₂)_(n)NR₁₁R₁₂; R₁₀ is selected from H, C₁₋₆alkyl, C₃₋₈cycloalkyl,wherein each alkyl or cycloalkyl is optionally substituted with phenyl,OH, C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂, or R₁₀ is phenyl optionallysubstituted with one to three C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(m)NR₈R₉, (CH₂)_(n)CONR₈R₉ or O(CH₂)₂₋₄NR₈R₉; R₁₁ and R₁₂ are eachindependently selected from H and C₁₋₆ alkyl optionally substituted withC₁₋₃alkoxy, OH or phenyl; or R₁₁ and R₁₂ together form a chaincompleting a ring, said chain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂; R₁₃ is H orC₁₋₃alkyl; P and Q are each independently CH or N; m is 1-4; n is 0-3;and p is 0-2; wherein one or more of the primary amine or secondaryamine nitrogen atoms in any of the R₄, R₅, R₆ and R₇ substituent groupsmay optionally be protected by a protecting group; and thepharmaceutically acceptable derivatives thereof.
 2. A compound accordingto claim 1 wherein: Ar₁ is a) a cycloalkyl group selected fromcyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl;b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, andcycloheptenyl; c) an aromatic carbocycle selected from phenyl, naphthyl,indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl, d) aheteroaryl selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl,isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl,benzothiazolyl, quinazolinyl, and indazolyl,or a fused heteroarylselected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine,cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine,cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline,cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole,cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; ore) a heterocycle selected from: pyrrolinyl, pyrrolidinyl, pyrazolinyl,pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl,thiopyranyl, piperazinyl and indolinyl; wherein each of the above Ar₁are optionally substituted by one or more R₁, R₂ and R₃; R₁ and R₂ areas defined in claim 1, and R₃ is H, halogen, methyl, methoxy,hydroxymethyl or OH; R₄ is H, C₁₋₃alkyl branched or unbranched,saturated or unsaturated, and optionally substituted with OH; or R₄ is(CH₂)₂₋₃NR₈R₉, (CH₂)_(n)CO₂R₁₀ or (CH₂)_(n)CONR₈R₉; R₅ is selected fromH, C₁₋₁₀alkyl branched or unbranched, C₃₋₁₀ cycloalkyl,C₅₋₇cycloalkenyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆acyl, each beingoptionally substituted with one or more halogen, OH, oxo, CN, C₁₋₆alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₃alkoxy, NR₈R₉, ureido, guanidino,NR₈COR₁₀, SR₁₀, CONR₈R₉, CO₂R₁₀, C₃₋₁₀ cycloalkyl,C₃₋₁₀-cycloalkylidene, C₅₋₇cycloalkenyl, aryloxy, arylthio, aryl,heteroaryl or heterocycle; wherein each of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl,aryloxy, arylthio, aryl, heteroaryl or heterocycle is optionallysubstituted with one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CN, NO₂,amidino, guanidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one ormore of the amino nitrogens in the ureido, amidino or guanidino groupsin this paragraph may be optionally substituted with C₁₋₃alkyl,phenylC₀₋₃alkyl, C₁₋₃alkoxy or CO₂R₁₀; or R₅ is selected from CO₂R₁₀,NR₈R₉, CONR₈R₉, aryl, heteroaryl, heterocycle, aryl-CO—, heteroaryl-CO—or heterocycle-CO—, wherein each aryl, heteroaryl or heterocycle isoptionally substituted with one to three: C₁₋₃alkoxy, halogen, NO₂, CN,S(O)_(p)NR₈R₉, C₀₋₃alkylS(O)_(p), NR₈R₉, (CH₂)_(n)CO₂R₁₀,(CH₂)_(n)CONR₈R₉, CO(CH₂)_(n)NR₈R₉, O(CH₂)₂₋₄NR₈R₉, ureido, guanidino,cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkyl-Z-, aryl-Z-,heteroaryl-Z-, heterocycle-Z-, or C₁₋₃alkyl optionally substituted withphenyl or NR₈R₉, wherein Z is a bridging group selected from C₁₋₁₀alkylene branched or unbranched, CO, S(O)_(p), O, S, NH, CONH, NHCO, COOor OOC, and wherein each cycloalkyl, aryl, heteroaryl or heterocycle isoptionally substituted with NO₂, C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CO₂R₁₀,(CH₂)_(n)NR₈R₉, O(CH₂)₂₋₄NR₈R₉, ureido or guanidino, wherein one or moreof the amino nitrogens in the ureido or guanidino groups in thisparagraph may be optionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkylor C₁₋₃alkoxy; and wherein each alkyl, alkoxy and phenyl in thisparagraph is optionally partially or fully halogenated; or R₅ is a C₆₋₁₂bridged- or spiro-bicyclic ring system, optionally having one or twodouble bonds in the ring system, and wherein up to 3 carbon atoms in thering system may be replaced by heteroatoms selected from N, O and S; andwherein said ring system may be optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, halogen, CO₂R₁₀, ureido, guanidino, amidino, (CH₂)_(n)NR₈R₉,or O(CH₂)₂₋₄NR₈R₉; wherein one or more of the amino nitrogens in theureido, guanidino or amidino groups in this paragraph may be optionallysubstituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy; R₆ isselected from H, C₁₋₆alkyl branched or unbranched, C₂₋₆ alkenyl branchedor unbranched, or CO₂R₁₀; wherein said C₁₋₆alkyl or C₁₋₆ alkenyl areoptionally substituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀,NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl, heteroaryl or heterocyclyl; R₇ is H orC₁₋₆alkyl; R₈ and R₉ are the same or different and are eachindependently selected from H, OH, C₁₋₃alkyl branched or unbranched,CO₂R₁₀, C₃₋₈cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl orheterocycle; wherein said alkyl, cycloalkyl, phenyl, benzyl, benzoyl,heteroaryl or heterocycle are optionally substituted with OH,C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀, NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl orheteroaryl; or R₈ and R₉ together form a 3-7 member alkylene chaincompleting a ring about the N atom to which they are attached; whereinsaid alkylene chain is optionally interrupted by O, S(O)_(p), NCOR₁₀,NCO₂R₁₀, NR₁₁ or NC(═NR₁₁)NR₁₁R₁₂; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₁R₁₂; R₁₀ is Hor C₁₋₆alkyl optionally substituted with phenyl, OH, C₁₋₃alkoxy,C₁₋₃alkanoyloxy or NR₁₁R₁₂; R₁₁ and R₁₂ are each independently selectedfrom H and C₁₋₆ alkyl optionally substituted with C₁₋₃alkoxy, OH orphenyl; or R₁₁ and R₁₂ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂; R₁₃ is H; and P and Q are each CH.3. A compound according to claim 2 wherein: Ar₁ is phenyl or pyridyl,each optionally substituted by one or more R₁, R₂ and R₃; X is NH orN—C₁₋₃alkyl; Y is NH; R₁ and R₂ are the same or different and selectedfrom: halogen, C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionallypartially or fully halogenated, NO₂ or NR₈R₉; R₃ is H, halogen, methylor methoxy; R₄ is H, C₁₋₃alkyl branched or unbranched, saturated orunsaturated, and optionally substituted with OH; or R₄ is (CH₂)₂₋₃NR₈R₉or CO₂R₁₀; R₅ is selected from H, C₁₋₃alkyl branched or unbranched, C₃₋₈cycloalkyl, C₅₋₇cycloalkenyl or C₂₋₄ alkenyl, each being optionallysubstituted with one or more OH, CN, NR₈R₉, CONR₈R₉, C₃₋₈ cycloalkyl,C₅₋₇cycloalkenyl, phenyl, heteroaryl or heterocycle; wherein eachphenyl, heteroaryl or heterocycle is optionally substituted with one ormore C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CN, NO₂, amidino, guanidino,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one or more of the aminonitrogens in the amidino or guanidino groups in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl, C₁₋₃alkoxy orCO₂R₁₀; or R₅ is selected from CO₂R₁₀, NR₈R₉, CONR₈R₉, phenyl, furyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl,benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl, or indolyl-CO—,wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, benzofuranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl,pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl orindolyl-CO— is optionally substituted with one to three: halogen, NO₂,S(O)_(p)NR₈R₉, C₀₋₃alkylS(O)_(p), NR₈R₉, (CH₂)_(n)CO₂R₁₀, ureido,guanidino, cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Z-,phenyl-Z-, heteroaryl-Z-, heterocycle-Z-, or C₁₋₃alkyl optionallysubstituted with phenyl or NR₈R₉, wherein Z is a bridging group selectedfrom C₁₋₃ alkylene branched or unbranched, O, S(O)_(p) or NH, andwherein each cycloalkyl, phenyl, heteroaryl or heterocycle is optionallysubstituted with NO₂, C₁₋₃alkyl, C₁₋₃alkoxy, CO₂R₁₀, (CH₂)_(n)NR₈R₉,O(CH₂)₂₋₄NR₈R₉ or guanidino, wherein one or more of the amino nitrogensin the guanidino group in this paragraph may be optionally substitutedwith C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy; and wherein each alkyl,alkoxy and phenyl in this paragraph is optionally partially or fullyhalogenated; or R₅ is a C₆₋₇ bridged-bicyclic ring system, optionallyhaving one or two double bonds in the ring system, and wherein up to 1carbon atom in the ring system may be replaced by a nitrogen atom; andwherein said ring system may be optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, halogen, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; R₆ is selectedfrom H, C₁₋₆alkyl branched or unbranched or CO₂R₁₀; R₇ is H orC₁₋₆alkyl; R₈ and R₉ are the same or different and are eachindependently selected from H, C₁₋₃alkyl branched or unbranched, CO₂R₁₀,phenyl, or benzoyl; wherein said alkyl, phenyl or benzoyl are optionallysubstituted with OH or C₁₋₃alkoxy; or R₈ and R₉ together form a—(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂— group, a —(CH₂)₂—N(COR₁₀)—(CH₂)₂— group, a—(CH₂)₂—N(R₁₁)—(CH₂)₂— group or a —(CH₂)₂—N(C(═NR₁₁)NR₁₁R₁₂)—(CH₂)₂—group; and wherein said ring is optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy, or OH; R₁₀ is H or C₁₋₆alkyl optionally substituted withphenyl, OH, C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂; R₁₁ and R₁₂ are eachindependently selected from H and C₁₋₃ alkyl optionally substituted withC₁₋₃alkoxy or OH; or R₁₁ and R₁₂ together form a chain completing aring, said chain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂.
 4. A compound accordingto claim 3 wherein: Ar₁ is phenyl; R₁ and R₂ are the same or differentand selected from: halogen, methyl optionally partially or fullyhalogenated, NO₂ and NH₂; R₃ is H, chloro, fluoro, bromo or methoxy; R₅is selected from C₂₋₄ alkenyl, C₃₋₈ cycloalkyl or C₅₋₇cycloalkenyl, eachbeing optionally substituted with one or more OH, CN, NR₈R₉, CONR₈R₉ orphenyl; wherein phenyl is optionally substituted with one or moreC₁₋₃alkyl, C₁₋₃alkoxy, halogen, amidino, guanidino, (CH₂)_(n)NR₈R₉, orO(CH₂)₂₋₄NR₈R₉; wherein one or more of the amino nitrogens in theamidino or guanidino groups in this paragraph may be optionallysubstituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy; or R₅ isselected from phenyl, furyl, thienyl, oxazolyl, thiazolyl, pyridinyl,benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-CO—, whereineach phenyl, furyl, thienyl, oxazolyl, thiazolyl, pyridinyl,benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-CO— isoptionally substituted with one to two: halogen, NO₂, SO₂NR₈R₉, NR₈R₉,(CH₂)_(n)CO₂R₁₀, ureido, cycloalkyl, phenyl, heteroaryl, heterocycle,cycloalkyl-Z-, heteroaryl-Z- or heterocycle-Z-, or C₁₋₃alkyl optionallysubstituted with NR₈R₉, wherein Z is a bridging group selected from C₁₋₃alkylene branched or unbranched or S(O)_(p), wherein each cycloalkyl,phenyl, heteroaryl or heterocycle is optionally substituted with NO₂,C₁₋₃alkyl, CO₂R₁₀, NR₈R₉ or guanidino, wherein one or more of the aminonitrogens in the guanidino group in this paragraph may be optionallysubstituted with C₁₋₃alkyl; and wherein each alkyl and phenyl in thisparagraph is optionally partially or fully halogenated; or R₅ is a7-azabicyclo[2.2.1]heptane ring system, optionally having one or twodouble bonds in the ring system, wherein said ring system may beoptionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; R₆ is selected from H or C₁₋₃alkylbranched or unbranched; R₇ is H or C₁₋₃alkyl; R₈ and R₉ are the same ordifferent and are each independently selected from H or C₁₋₃alkylbranched or unbranched; wherein said alkyl is optionally substitutedwith OH or C₁₋₃alkoxy; or R₈ and R₉ together form a—(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂—, a —(CH₂)₂—N(COR₁₀)—(CH₂)₂— group, a—(CH₂)₂—N(R₁₁)—(CH₂)₂— group or a —(CH₂)₂—N(C(═NR₁₁)NR₁₁R₁₂)—(CH₂)₂—group; and wherein said ring is optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy, or OH; R₁₀ is H or C₁₋₃alkyl optionally substituted withphenyl, OH or C₁₋₃alkanoyloxy; and R₁₁ is selected from H and C₁₋₃alkyl.
 5. A compound according to any of claims 1, 2, 3 or 4, whereinthe Het represents a fused ring having formula B:

wherein R₅ is as defined in claims 1, 2, 3 or
 4. 6. A compound accordingto claim 1, represented by the following formula (I′):

wherein R₁, R₂, R₃, X, P, Q and Het are as defined in claim 1; and thepharmaceutically acceptable derivatives thereof.
 7. A compound accordingto claim 6 wherein: X is NH or N—C₁₋₃alkyl; R₁ and R₂ are the same ordifferent and selected from: halogen, C₁₋₃ alkyl, wherein the C₁₋₃ alkylis optionally partially or fully halogenated, NO₂ or NR₈R₉; R₃ is H,halogen, methyl or methoxy; R₄ is H, C₁₋₃alkyl branched or unbranched,saturated or unsaturated, and optionally substituted with OH; or R₄ is(CH₂)₂₋₃NR₈R₉ or CO₂R₁₀; R₅ is selected from H, C₁₋₃alkyl branched orunbranched, C₃₋₈ cycloalkyl, C₅₋₇cycloalkenyl or C₂₋₄ alkenyl, eachbeing optionally substituted with one or more OH, CN, NR₈R₉, CONR₈R₉,C₃₋₈ cycloalkyl, C₅₋₇cycloalkenyl, phenyl, heteroaryl or heterocycle;wherein each phenyl, heteroaryl or heterocycle is optionally substitutedwith one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CN, NO₂, amidino,guanidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one or more of theamino nitrogens in the amidino or guanidino groups in this paragraph maybe optionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl, C₁₋₃alkoxy orCO₂R₁₀; or R₅ is selected from CO₂R₁₀, NR₈R₉, CONR₈R₉, phenyl, furyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl,benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl, or indolyl-CO—,wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, benzofuranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl,pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl orindolyl-CO— is optionally substituted with one to three: halogen, NO₂,S(O)_(p)NR₈R₉, C₀₋₃alkylS(O)_(p), NR₈R₉, (CH₂)_(n)CO₂R₁₀, ureido,guanidino, cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Z-,phenyl-Z-, heteroaryl-Z-, heterocycle-Z-, or C₁₋₃alkyl optionallysubstituted with phenyl or NR₈R₉, wherein Z is a bridging group selectedfrom C₁₋₃ alkylene branched or unbranched, O, S(O)_(p) or NH, andwherein each cycloalkyl, phenyl, heteroaryl or heterocycle is optionallysubstituted with NO₂, C₁₋₃alkyl, C₁₋₃alkoxy, CO₂R₁₀, (CH₂)_(n)NR₈R₉,O(CH₂)₂₋₄NR₈R₉ or guanidino, wherein one or more of the amino nitrogensin the guanidino group in this paragraph may be optionally substitutedwith C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy; and wherein each alkyl,alkoxy and phenyl in this paragraph is optionally partially or fullyhalogenated; or R₅ is a C₆₋₇ bridged-bicyclic ring system, optionallyhaving one or two double bonds in the ring system, and wherein up to 1carbon atom in the ring system may be replaced by a nitrogen atom; andwherein said ring system may be optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, halogen, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; R₆ is selectedfrom H, C₁₋₆alkyl branched or unbranched or CO₂R₁₀; R₇ is H orC₁₋₆alkyl; R₈ and R₉ are the same or different and are eachindependently selected from H, C₁₋₃alkyl branched or unbranched, CO₂R₁₀,phenyl, or benzoyl; wherein said alkyl, phenyl or benzoyl are optionallysubstituted with OH or C₁₋₃alkoxy; or R₈ and R₉ together form a—(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂— group, a —(CH₂)₂—N(COR₁₀)—(CH₂)₂— group, a—(CH₂)₂—N(R₁₁)—(CH₂)₂— group or a —(CH₂)₂—N(C(═NR₁₁)NR₁₁R₁₂)—(CH₂)₂—group; and wherein said ring is optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy, or OH; R₁₀ is H or C₁₋₆alkyl optionally substituted withphenyl, OH, C₁₋₃alkoxy, C₁₋₃alkanoyloxy or NR₁₁R₁₂; R₁₁ and R₁₂ are eachindependently selected from H and C₁₋₃ alkyl optionally substituted withC₁₋₃alkoxy or OH; or R₁₁ and R₁₂ together form a chain completing aring, said chain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂; and P and Q are each CH.8. A compound according to claim 7, wherein R₁ and R₂ are the same ordifferent and selected from: halogen, methyl optionally partially orfully halogenated, NO₂ and NH₂; R₃ is H, chloro, fluoro, bromo ormethoxy; R₅ is selected from C₂₋₄ alkenyl, C₃₋₈ cycloalkyl orC₅₋₇cycloalkenyl, each being optionally substituted with one or more OH,CN, NR₈R₉, CONR₈R₉ or phenyl; wherein phenyl is optionally substitutedwith one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen, amidino, guanidino,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one or more of the aminonitrogens in the amidino or guanidino groups in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy; orR₅ is selected from phenyl, furyl, thienyl, oxazolyl, thiazolyl ,pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-CO—, whereineach phenyl, furyl, thienyl, oxazolyl, thiazolyl, pyridinyl,benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-CO— isoptionally substituted with one to two: halogen, NO₂, SO₂NR₈R₉, NR₈R₉,(CH₂)_(n)CO₂R₁₀, ureido, cycloalkyl, phenyl, heteroaryl, heterocycle,cycloalkyl-Z-, heteroaryl-Z- or heterocycle-Z-, or C₁₋₃alkyl optionallysubstituted with NR₈R₉, wherein Z is a bridging group selected from C₁₋₃alkylene branched or unbranched or S(O)_(p), wherein each cycloalkyl,phenyl, heteroaryl or heterocycle is optionally substituted with NO₂,C₁₋₃alkyl, CO₂R₁₀, NR₈R₉ or guanidino, wherein one or more of the aminonitrogens in the guanidino group in this paragraph may be optionallysubstituted with C₁₋₃alkyl; and wherein each alkyl and phenyl in thisparagraph is optionally partially or fully halogenated; or R₅ is a7-azabicyclo[2.2.1]heptane ring system, optionally having one or twodouble bonds in the ring system, wherein said ring system may beoptionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; R₆ is selected from H or C₁₋₃alkylbranched or unbranched; R₇ is H or C₁₋₃alkyl; R₈ and R₉ are the same ordifferent and are each independently selected from H or C₁₋₃alkylbranched or unbranched; wherein said alkyl is optionally substitutedwith OH or C₁₋₃alkoxy; or R₈ and R₉ together form a—(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂—, a —(CH₂)₂—N(COR₁₀)—(CH₂)₂— group, a—(CH₂)₂—N(R₁₁)—(CH₂)₂— group or a —(CH₂)₂—N(C(═NR₁₁)NR₁₁R₁₂)—(CH₂)₂—group; and wherein said ring is optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy, or OH; R₁₀ is H or C₁₋₃alkyl optionally substituted withphenyl, OH or C₁₋₃alkanoyloxy; and R₁₁ is selected from H and C₁₋₃alkyl.
 9. A compound according to any of claims 6, 7 or 8, wherein theHet represents a fused ring having formula B:

wherein R₅ is as defined in claims 6, 7 or
 8. 10. A compound accordingto claim 1, represented by the following formula (Ib):

wherein R is H, C₁₋₃alkyl or cyclopropyl, and Ar₁ and R₅ are as definedin claim 1; and the pharmaceutically acceptable derivatives thereof. 11.A compound selected from the group consisting of:2-(2,6-Dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-7-furan-2-yl-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-phenyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-nitrophenyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;7-(3-Aminophenyl)-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;1-{3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-phenyl}-3-ethylurea;2-(2,6-Dichlorophenylamino)-1-methyl-7-vinyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-thiophen-2-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-[2-(3-nitrophenyl)-thiazol-4-yl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-7-imidazol-2-yl-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-phenyloxazol-5-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazoline-7-carboxamide;2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-methylpropen-1-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-pyridin-2-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-pyridin-3-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-1H-imidazo[4,5-f]quinazoline-7,9-6H,8H-dione;2-(2,6-Dichlorophenylamino)-1-methyl-7-propen-2-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;7-Cyclopent-1-enyl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;7-[2-(3-Aminophenyl)-thiazol-4-yl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;Ethyl 2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazoline-7-carboxylate;7-Benzofuran-2yl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-(1-methylprop-1-enyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-methyloxazol-5-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-7-(1H-indole-3-carbonyl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-piperazin-1-yl-cyclopent-1-enyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;7-Cyclohex-1-enyl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-[5-(2-nitrophenyl)-furan-2-yl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-7-furan-3-yl-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;7-(5-Bromofuran-2-yl)-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-methylfuran-2-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;7-Cyclopropyl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-[3-(4-methylpiperazine-1-sulfonyl)-phenyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;4-{3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-cyclopent-2-enyl}-piperazine-1-carboxylicacid tert-butyl ester;2-(2,6-Dichlorophenylamino)-7-(3-hydroxycyclopent-1-enyl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-[3-(piperazine-1-sulfonyl)-phenyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-cyclopent-3-enecarbonitrile;7-Amino-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;3-{2-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-propenyl}-benzonitrile;3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-cyclopent-3-enecarboxamide;2-{4-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-thiazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester;2-(2,6-Dichlorophenylamino)-1-methyl-7-[1-methyl-2-(3-nitrophenyl)-vinyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;3-{4-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-thiazol-2-ylmethyl}-piperidine-1-carboxylicacid benzyl ester;7-[2-(2-Aminocyclohexyl)-thiazol-4-yl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-piperidin-3-ylmethyl-thiazol-4-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-methylthiazol-4-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-oxocyclopent-1-enyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-2,5-dihydro-pyrrole-1-carboxylicacid tert-butyl ester; 7-[2-(3-Aminophenyl)-1-methylvinyl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;Acetic acid2-(4-{3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-benzenesulfonyl}-piperazin-1-yl)-2-oxoethyl ester;2-(2,6-Dichlorophenylamino)-7-(2,5-dihydro-1H-pyrrol-3-yl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;7-[2-(3-Aminomethylphenyl)-1-methylvinyl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;4-{3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-benzenesulfonyl}-piperazine-1-carboxamidine;2-(2,6-Dichlorophenylamino)-7-{3-[4-(2-hydroxyacetyl)-piperazine-1-sulfonyl]-phenyl}-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;3-{2-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-propenyl}-benzamidine;7-(7-Azabicyclo[2.2.1]hepta-2,5-dien-2-yl)-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;5-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester;2-(2,6-Dichlorophenylamino)-7-(1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrol-5-yl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-pyrrolidin-2yl-thiazol-4-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;7-[2-(3,5-Diaminophenyl)-1-methylvinyl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;and2-(2,6-Dichlorophenylamino)-1-methyl-7-[4-(piperazine-1-sulfonyl)-phenyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;and the pharmaceutically acceptable derivatives thereof.
 12. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claims 1, 6 or
 10. 13. A method of treatingan autoimmune disease, cancer or a cerebral ischemic condition saidmethod comprising administering to a patient in need thereof atherapeutically effective amount of a compound according to claims 1, 6or
 10. 14. A method according to claim 13, wherein the autoimmunedisease is selected from rheumatoid arthritis, multiple sclerosis,Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis,graft versus host disease, systemic lupus erythematosus,insulin-dependent diabetes mellitus and asthma.
 15. A method accordingto claim 13, wherein the cancer is selected from a src-dependent tumoror a PDGF-dependent tumor.
 16. A method according to claim 15, whereinthe src-dependent tumor is selected from mammary carcinoma, coloncarcinoma, melanoma and sarcoma.
 17. A method according to claim 15,wherein the PDGF-dependent tumor is selected from ovarian cancer,prostate cancer and glioblastoma.
 18. A method according to claim 13,wherein the cerebral ischemic condition is stroke.
 19. A method oftreating a disease selected from osteoporosis, Paget's disease, boneinflammation, and joint inflammation, said method comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to claims 1, 6 or
 10. 20. A method oftreating a disease selected from fibrotic diseases, restenosis andatherosclerosis, said method comprising administering to a patient inneed thereof a therapeutically effective amount of a compound accordingto claims 1, 6 or
 10. 21. A method of enhancing or potentiating theeffectiveness of radiation therapy by administering to a patientundergoing such therapy a therapeutically effective amount of compoundaccording to claims 1, 6 or
 10. 22. A compound of the following formulaVI:

wherein: R is H, C₁₋₃alkyl or cyclopropyl; R₄ is selected from H, C₁₋₆alkyl branched or unbranched, saturated or unsaturated, and optionallysubstituted with phenyl, OH or C₁₋₃alkoxy; or R₄ is selected from(CH₂)_(m)NR₈R₉, (CH₂)_(m)NR₈COR₁₀, (CH₂)_(n)CO₂R₁₀ or (CH₂)_(n)CONR₈R₉;R₈, R₉, R₁₀ and m are as defined in claim 1; and n is 1-3; wherein oneor more of the primary amine or secondary amine nitrogen atoms in the R₄substituent group may optionally be protected by a protecting group. 23.A compound according to claim 22, wherein R is H or C₁₋₃alkyl; R₄ is H,C₁₋₃alkyl branched or unbranched, saturated or unsaturated, andoptionally substituted with OH; or R₄ is (CH₂)₂₋₃NR₈R₉, (CH₂)_(n)CO₂R₁₀or (CH₂)_(n)CONR₈R₉.
 24. A compound of the following formula XII:

wherein: R is H, C₁₋₃alkyl or cyclopropyl; and R₅ is as defined inclaim
 1. 25. A compound according to claim 24, wherein: R is H orC₁₋₃alkyl; R₅ is selected from H, C₁₋₃alkyl branched or unbranched, C₃₋₈cycloalkyl, C₅₋₇cycloalkenyl or C₂₋₄ alkenyl, each being optionallysubstituted with one or more OH, CN, NR₈R₉, CONR₈R₉, C₃₋₈ cycloalkyl,C₅₋₇cycloalkenyl, phenyl, heteroaryl or heterocycle; wherein eachphenyl, heteroaryl or heterocycle is optionally substituted with one ormore C₁₋₃alkyl, C₁₋₃alkoxy, halogen, CN, NO₂, amidino, guanidino,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one or more of the aminonitrogens in the amidino or guanidino groups in this paragraph may beoptionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkyl, C₁₋₃alkoxy orCO₂R₁₀; or R₅ is selected from CO₂R₁₀, NR₈R₉, CONR₈R₉, phenyl, furyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl,benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl, or indolyl-CO—,wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, benzofuranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl,pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl orindolyl-CO— is optionally substituted with one to three: halogen, NO₂,S(O)_(p)NR₈R₉, C₀₋₃alkylS(O)_(p), NR₈R₉, (CH₂)_(n)CO₂R₁₀, ureido,guanidino, cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Z-,phenyl-Z-, heteroaryl-Z-, heterocycle-Z-, or C₁₋₃alkyl optionallysubstituted with phenyl or NR₈R₉, wherein Z is a bridging group selectedfrom C₁₋₃ alkylene branched or unbranched, O, S(O)_(p) or NH, andwherein each cycloalkyl, phenyl, heteroaryl or heterocycle is optionallysubstituted with NO₂, C₁₋₃alkyl, C₁₋₃alkoxy, CO₂R₁₀, (CH₂)_(n)NR₈R₉,O(CH₂)₂₋₄NR₈R₉ or guanidino, wherein one or more of the amino nitrogensin the guanidino group in this paragraph may be optionally substitutedwith C₁₋₃alkyl, phenylC₀₋₃alkyl or C₁₋₃alkoxy; and wherein each alkyl,alkoxy and phenyl in this paragraph is optionally partially or fullyhalogenated; or R₅ is a C₆₋₇ bridged-bicyclic ring system, optionallyhaving one or two double bonds in the ring system, and wherein up to 1carbon atom in the ring system may be replaced by a nitrogen atom; andwherein said ring system may be optionally substituted with C₁₋₃alkyl,C₁₋₃alkoxy, halogen, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; 25 A compoundaccording to claim 24, wherein: R₅ is selected from C₂₋₄ alkenyl, C₃₋₈cycloalkyl or C₅₋₇cycloalkenyl, each being optionally substituted withone or more OH, CN, NR₈R₉, CONR₈R₉ or phenyl; wherein phenyl isoptionally substituted with one or more C₁₋₃alkyl, C₁₋₃alkoxy, halogen,amidino, guanidino, (CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉; wherein one ormore of the amino nitrogens in the amidino or guanidino groups in thisparagraph may be optionally substituted with C₁₋₃alkyl, phenylC₀₋₃alkylor C₁₋₃alkoxy; or R₅ is selected from phenyl, furyl, thienyl, oxazolyl,thiazolyl , pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl,pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl orindolyl-CO—, wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl,pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl,1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-CO— isoptionally substituted with one to two: halogen, NO₂, SO₂NR₈R₉, NR₈R₉,(CH₂)_(n)CO₂R₁₀, ureido, cycloalkyl, phenyl, heteroaryl, heterocycle,cycloalkyl-Z-, heteroaryl-Z- or heterocycle-Z-, or C₁₋₃alkyl optionallysubstituted with NR₈R₉, wherein Z is a bridging group selected from C₁₋₃alkylene branched or unbranched or S(O)_(p), wherein each cycloalkyl,phenyl, heteroaryl or heterocycle is optionally substituted with NO₂,C₁₋₃alkyl, CO₂R₁₀, NR₈R₉ or guanidino, wherein one or more of the aminonitrogens in the guanidino group in this paragraph may be optionallysubstituted with C₁₋₃alkyl; and wherein each alkyl and phenyl in thisparagraph is optionally partially or fully halogenated; or R₅ is a7-azabicyclo[2.2.1]heptane ring system, optionally having one or twodouble bonds in the ring system, wherein said ring system may beoptionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(n)NR₈R₉, or O(CH₂)₂₋₄NR₈R₉.
 26. A method of making a compound ofthe formula Ib below:

wherein R is H, C₁₋₃alkyl or cyclopropyl, and Ar₁ and R₅ are as definedin claim 1, said method comprising: (a) reacting the compound of formulaXIX (wherein R₄ is H) with an acid halide of the formula R₅COX, whereinX is a halogen, or with an acid anhydride of the formula (R₅CO)₂O, orwith an acid of the formula R₅CO₂H and a coupling reagent, in a suitablesolvent in the presence of a suitable base to form a compound of formulaXXI:

(b) cyclizing the compound of formula XXI by treatment with a suitablebase in a suitable solvent at about reflux temperature to form acompound of formula Ib:


27. A method of making a compound of the formula Ib below:

wherein R is H, C₁₋₃alkyl or cyclopropyl, and Ar₁ and R₅ are as definedin claim 1, said method comprising: (a) reacting the compound of formulaXIX (wherein R₄ is H) with an aldehyde of the formula R₅CHO in thepresence of an acid in a suitable solvent to form a compound of formulaId:

(b) oxidizing the compound of formula Id with a suitable oxidizing agentto form the compound of formula Ib:


28. A method of making a compound of the formula Ib below:

wherein R is H, C₁₋₃alkyl or cyclopropyl, and Ar₁ and R₅ are as definedin claim 1, said method comprising: (a) reacting the compound of formulaXVIII (wherein R₄ is H) with an acid halide of the formula R₅COX,wherein X is a halogen, or with an acid anhydride of the formula(R₅CO)₂O, or with an acid of the formula R₅CO₂H and a coupling reagent,in a suitable solvent in the presence of a suitable base to form acompound of formula XX:

(b) hydrolyzing and cyclizing the compound of formula XX by treatmentwith a suitable base and a suitable oxidant in a suitable solvent toform the compound of formula Ib:


29. A compound of the following formula XVIII:

wherein: Ar₁ is as defined in claim 1; R is H, C₁₋₃alkyl or cyclopropyl;and R₄ is as defined in claim
 1. 30. A compound according to claim 29,wherein: Ar₁ is a) a cycloalkyl group selected from cyclopropyl,cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl; b) acycloalkenyl group selected from cyclopentenyl, cyclohexenyl, andcycloheptenyl; c) an aromatic carbocycle selected from phenyl, naphthyl,indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl, d) aheteroaryl selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl,isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl,benzothiazolyl, quinazolinyl, and indazolyl,or a fused heteroarylselected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine,cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine,cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline,cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole,cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; ore) a heterocycle selected from: pyrrolinyl, pyrrolidinyl, pyrazolinyl,pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl,thiopyranyl, piperazinyl and indolinyl; wherein each of the above Ar₁are optionally substituted by one or more R₁, R₂ and R₃; R₁ and R₂ areas defined in claim 1, and R₃ is hydrogen, halogen, methyl, methoxy,hydroxymethyl or OH; and R₄ is H, C₁₋₃alkyl branched or unbranched,saturated or unsaturated, and optionally substituted with OH; or R₄ is(CH₂)₂₋₃NR₈R₉, (CH₂)_(n)CO₂R₁₀ or (CH₂)_(n)CONR₈R₉; R₈ and R₉ are thesame or different and are each independently selected from H, OH,C₁₋₃alkyl branched or unbranched, CO₂R₁₀, C₃₋₈cycloalkyl, phenyl,benzyl, benzoyl, heteroaryl or heterocycle; wherein said alkyl,cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl or heterocycle areoptionally substituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀,NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl or heteroaryl; or R₈ and R₉ togetherform a 4-6 member alkylene chain completing a ring about the N atom towhich they are attached; wherein said alkylene chain is optionallyinterrupted by NCO₂R₁₀ or NR₁₁; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₁R₁₂; R₁₀ is Hor C₁₋₆alkyl optionally substituted with phenyl, OH, C₁₋₃alkoxy orNR₁₁R₁₂; R₁₁ and R₁₂ are each independently selected from H and C₁₋₆alkyl optionally substituted with C₁₋₃alkoxy, OH or phenyl; or R₁₁ andR₁₂ together form a chain completing a ring, said chain is (CH₂)₄₋₅ or(CH₂)₂O(CH₂)₂; and n is 0-3.
 31. A compound according to claim 30,wherein: Ar₁ is phenyl or pyridyl, each optionally substituted by one ormore R₁, R₂ and R₃; R is H or C₁₋₃alkyl; R₁ and R₂ are the same ordifferent and selected from: halogen, C₁₋₃ alkyl, wherein the C₁₋₃ alkylis optionally partially or fully halogenated, NO₂ or NR₈R₉; R₃ is H,halogen, methyl or methoxy; R₄ is H, C₁₋₃alkyl branched or unbranched,saturated or unsaturated, and optionally substituted with OH; or R₄ is(CH₂)₂₋₃NR₈R₉ or CO₂R₁₀; R₈ and R₉ are the same or different and areeach independently selected from H, C₁₋₃alkyl branched or unbranched,CO₂R₁₀, phenyl, or benzoyl; wherein said alkyl, phenyl or benzoyl areoptionally substituted with OH or C₁₋₃alkoxy; or R₈ and R₉ together forma —(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂— group or a —(CH₂)₂—N(R₁₁)—(CH₂)₂— group; andwherein said ring is optionally substituted by C₁₋₃ alkyl, C₁₋₃alkoxy,or OH; R₁₀ is H or C₁₋₃alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy or NR₁₁R₁₂; R₁₁ and R₁₂ are each independently selected fromH and C₁₋₃ alkyl optionally substituted with C₁₋₃alkoxy or OH; or R₁₁and R₁₂ together form a chain completing a ring, said chain is (CH₂)₄₋₅or (CH₂)₂O(CH₂)₂.
 32. A compound of the following formula XIX:

wherein: Ar₁ is as defined in claim 1; R is H, C₁₋₃alkyl or cyclopropyl;and R₄ is as defined in claim
 1. 33. A compound according to claim 32,wherein: Ar₁ is a) a cycloalkyl group selected from cyclopropyl,cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl; b) acycloalkenyl group selected from cyclopentenyl, cyclohexenyl, andcycloheptenyl; c) an aromatic carbocycle selected from phenyl, naphthyl,indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl, d) aheteroaryl selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl,isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl,benzothiazolyl, quinazolinyl, and indazolyl,or a fused heteroarylselected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine,cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine,cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline,cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole,cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; ore) a heterocycle selected from: pyrrolinyl, pyrrolidinyl, pyrazolinyl,pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl,thiopyranyl, piperazinyl and indolinyl; wherein each of the above Ar₁are optionally substituted by one or more R₁, R₂ and R₃; R₁ and R₂ areas defined in claim 1, and R₃ is hydrogen, halogen, methyl, methoxy,hydroxymethyl or OH; and R₄ is H, C₁₋₃alkyl branched or unbranched,saturated or unsaturated, and optionally substituted with OH; or R₄ is(CH₂)₂₋₃NR₈R₉, (CH₂)_(n)CO₂R₁₀ or (CH₂)_(n)CONR₈R₉; R₈ and R₉ are thesame or different and are each independently selected from H, OH,C₁₋₃alkyl branched or unbranched, CO₂R₁₀, C₃₋₈cycloalkyl, phenyl,benzyl, benzoyl, heteroaryl or heterocycle; wherein said alkyl,cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl or heterocycle areoptionally substituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₀,NR₁₁R₁₂, O(CH₂)₂₋₄NR₁₁R₁₂, aryl or heteroaryl; or R₈ and R₉ togetherform a 4-6 member alkylene chain completing a ring about the N atom towhich they are attached; wherein said alkylene chain is optionallyinterrupted by NCO₂R₁₀ or NR₁₁; and wherein said ring is optionallysubstituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₁R₁₂; R₁₀ is Hor C₁₋₆alkyl optionally substituted with phenyl, OH, C₁₋₃alkoxy orNR₁₁R₁₂; R₁₁ and R₁₂ are each independently selected from H and C₁₋₆alkyl optionally substituted with C₁₋₃alkoxy, OH or phenyl; or R₁₁ andR₁₂ together form a chain completing a ring, said chain is (CH₂)₄₋₅ or(CH₂)₂O(CH₂)₂; and n is 0-3.
 34. A compound according to claim 33,wherein: Ar₁ is phenyl or pyridyl, each optionally substituted by one ormore R₁, R₂ and R₃; R is H or C₁₋₃alkyl; R₁ and R₂ are the same ordifferent and selected from: halogen, C₁₋₃ alkyl, wherein the C₁₋₃ alkylis optionally partially or fully halogenated, NO₂ or NR₈R₉; R₃ is H,halogen, methyl or methoxy; R₄ is H, C₁₋₃alkyl branched or unbranched,saturated or unsaturated, and optionally substituted with OH; or R₄ is(CH₂)₂₋₃NR₈R₉ or CO₂R₁₀; R₈ and R₉ are the same or different and areeach independently selected from H, C₁₋₃alkyl branched or unbranched,CO₂R₁₀, phenyl, or benzoyl; wherein said alkyl, phenyl or benzoyl areoptionally substituted with OH or C₁₋₃alkoxy; or R₈ and R₉ together forma —(CH₂)₂—N(CO₂R₁₀)—(CH₂)₂— group or a —(CH₂)₂—N(R₁₁)—(CH₂)₂— group; andwherein said ring is optionally substituted by C₁₋₃ alkyl, C₁₋₃alkoxy,or OH; R₁₀ is H or C₁₋₃alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy or NR₁₁R₁₂; R₁₁ and R₁₂ are each independently selected fromH and C₁₋₃ alkyl optionally substituted with C₁₋₃alkoxy or OH; or R₁₁and R₁₂ together form a chain completing a ring, said chain is (CH₂)₄₋₅or (CH₂)₂O(CH₂)₂.